JP6639513B2 - Adhesive polymer and medical patch - Google Patents
Adhesive polymer and medical patch Download PDFInfo
- Publication number
- JP6639513B2 JP6639513B2 JP2017543622A JP2017543622A JP6639513B2 JP 6639513 B2 JP6639513 B2 JP 6639513B2 JP 2017543622 A JP2017543622 A JP 2017543622A JP 2017543622 A JP2017543622 A JP 2017543622A JP 6639513 B2 JP6639513 B2 JP 6639513B2
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- Prior art keywords
- meth
- acrylate
- hydrochloride
- star
- polymer
- Prior art date
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- 239000002998 adhesive polymer Substances 0.000 title description 6
- 229920000642 polymer Polymers 0.000 claims description 188
- 239000000178 monomer Substances 0.000 claims description 177
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 140
- 238000006116 polymerization reaction Methods 0.000 claims description 101
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 94
- 239000000203 mixture Substances 0.000 claims description 93
- 239000000243 solution Substances 0.000 claims description 83
- 239000003814 drug Substances 0.000 claims description 68
- 239000004820 Pressure-sensitive adhesive Substances 0.000 claims description 60
- -1 isooctyl Chemical group 0.000 claims description 54
- 125000004432 carbon atom Chemical group C* 0.000 claims description 46
- 238000004519 manufacturing process Methods 0.000 claims description 42
- 230000001070 adhesive effect Effects 0.000 claims description 41
- 239000000853 adhesive Substances 0.000 claims description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 33
- 150000003839 salts Chemical class 0.000 claims description 28
- 238000010526 radical polymerization reaction Methods 0.000 claims description 26
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical group SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims description 23
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims description 19
- ZWAPMFBHEQZLGK-UHFFFAOYSA-N 5-(dimethylamino)-2-methylidenepentanamide Chemical compound CN(C)CCCC(=C)C(N)=O ZWAPMFBHEQZLGK-UHFFFAOYSA-N 0.000 claims description 14
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 10
- JDBJJCWRXSVHOQ-UTONKHPSSA-N methanesulfonic acid;(1r)-n-prop-2-ynyl-2,3-dihydro-1h-inden-1-amine Chemical compound CS(O)(=O)=O.C1=CC=C2[C@H](NCC#C)CCC2=C1 JDBJJCWRXSVHOQ-UTONKHPSSA-N 0.000 claims description 10
- 229960001956 rasagiline mesylate Drugs 0.000 claims description 10
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 229920001577 copolymer Polymers 0.000 claims description 8
- 150000003254 radicals Chemical class 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- HDWNKEWYEDOKIZ-UHFFFAOYSA-N 5-(diethylamino)-2-methylidenepentanamide Chemical compound CCN(CC)CCCC(=C)C(N)=O HDWNKEWYEDOKIZ-UHFFFAOYSA-N 0.000 claims description 6
- MZVQCMJNVPIDEA-UHFFFAOYSA-N [CH2]CN(CC)CC Chemical group [CH2]CN(CC)CC MZVQCMJNVPIDEA-UHFFFAOYSA-N 0.000 claims description 6
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 5
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 5
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 5
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 4
- 150000003512 tertiary amines Chemical class 0.000 claims description 4
- BQNSLJQRJAJITR-UHFFFAOYSA-N 1,1,2-trichloro-1,2-difluoroethane Chemical compound FC(Cl)C(F)(Cl)Cl BQNSLJQRJAJITR-UHFFFAOYSA-N 0.000 claims description 3
- CIVCELMLGDGMKZ-UHFFFAOYSA-N 2,4-dichloro-6-methylpyridine-3-carboxylic acid Chemical compound CC1=CC(Cl)=C(C(O)=O)C(Cl)=N1 CIVCELMLGDGMKZ-UHFFFAOYSA-N 0.000 claims description 3
- ZZIZZTHXZRDOFM-UHFFFAOYSA-N 2-(2-ethoxyphenoxy)ethyl-[1-(4-methoxy-3-sulfamoylphenyl)propan-2-yl]azanium;chloride Chemical compound Cl.CCOC1=CC=CC=C1OCCNC(C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 ZZIZZTHXZRDOFM-UHFFFAOYSA-N 0.000 claims description 3
- MEAPRSDUXBHXGD-UHFFFAOYSA-N 3-chloro-n-(4-propan-2-ylphenyl)propanamide Chemical compound CC(C)C1=CC=C(NC(=O)CCCl)C=C1 MEAPRSDUXBHXGD-UHFFFAOYSA-N 0.000 claims description 3
- YYSCJLLOWOUSHH-UHFFFAOYSA-N 4,4'-disulfanyldibutanoic acid Chemical compound OC(=O)CCCSSCCCC(O)=O YYSCJLLOWOUSHH-UHFFFAOYSA-N 0.000 claims description 3
- MKBLHFILKIKSQM-UHFFFAOYSA-N 9-methyl-3-[(2-methyl-1h-imidazol-3-ium-3-yl)methyl]-2,3-dihydro-1h-carbazol-4-one;chloride Chemical compound Cl.CC1=NC=CN1CC1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 MKBLHFILKIKSQM-UHFFFAOYSA-N 0.000 claims description 3
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 claims description 3
- ZNIFSRGNXRYGHF-UHFFFAOYSA-N Clonidine hydrochloride Chemical compound Cl.ClC1=CC=CC(Cl)=C1NC1=NCCN1 ZNIFSRGNXRYGHF-UHFFFAOYSA-N 0.000 claims description 3
- XIQVNETUBQGFHX-UHFFFAOYSA-N Ditropan Chemical compound C=1C=CC=CC=1C(O)(C(=O)OCC#CCN(CC)CC)C1CCCCC1 XIQVNETUBQGFHX-UHFFFAOYSA-N 0.000 claims description 3
- 108010061435 Enalapril Proteins 0.000 claims description 3
- HCBIBCJNVBAKAB-UHFFFAOYSA-N Procaine hydrochloride Chemical compound Cl.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 HCBIBCJNVBAKAB-UHFFFAOYSA-N 0.000 claims description 3
- XDXHAEQXIBQUEZ-UHFFFAOYSA-N Ropinirole hydrochloride Chemical compound Cl.CCCN(CCC)CCC1=CC=CC2=C1CC(=O)N2 XDXHAEQXIBQUEZ-UHFFFAOYSA-N 0.000 claims description 3
- UHSKFQJFRQCDBE-UHFFFAOYSA-N Ropinirole hydrochloride Natural products CCCN(CCC)CCC1=CC=CC2=C1CC(=O)N2 UHSKFQJFRQCDBE-UHFFFAOYSA-N 0.000 claims description 3
- RSLNRVYIRDVHLY-UHFFFAOYSA-N Tulobuterol hydrochloride Chemical compound [Cl-].CC(C)(C)[NH2+]CC(O)C1=CC=CC=C1Cl RSLNRVYIRDVHLY-UHFFFAOYSA-N 0.000 claims description 3
- DOQPXTMNIUCOSY-UHFFFAOYSA-N [4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]-[2-(3,4-dimethoxyphenyl)ethyl]-methylazanium;chloride Chemical compound [H+].[Cl-].C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 DOQPXTMNIUCOSY-UHFFFAOYSA-N 0.000 claims description 3
- BNPSSFBOAGDEEL-UHFFFAOYSA-N albuterol sulfate Chemical compound OS(O)(=O)=O.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 BNPSSFBOAGDEEL-UHFFFAOYSA-N 0.000 claims description 3
- WOLHOYHSEKDWQH-UHFFFAOYSA-N amantadine hydrochloride Chemical compound [Cl-].C1C(C2)CC3CC2CC1([NH3+])C3 WOLHOYHSEKDWQH-UHFFFAOYSA-N 0.000 claims description 3
- 229960001280 amantadine hydrochloride Drugs 0.000 claims description 3
- YEJAJYAHJQIWNU-UHFFFAOYSA-N azelastine hydrochloride Chemical compound Cl.C1CN(C)CCCC1N1C(=O)C2=CC=CC=C2C(CC=2C=CC(Cl)=CC=2)=N1 YEJAJYAHJQIWNU-UHFFFAOYSA-N 0.000 claims description 3
- 229960004335 azelastine hydrochloride Drugs 0.000 claims description 3
- VHYCDWMUTMEGQY-UHFFFAOYSA-N bisoprolol Chemical compound CC(C)NCC(O)COC1=CC=C(COCCOC(C)C)C=C1 VHYCDWMUTMEGQY-UHFFFAOYSA-N 0.000 claims description 3
- 229960002781 bisoprolol Drugs 0.000 claims description 3
- 229960001889 buprenorphine hydrochloride Drugs 0.000 claims description 3
- GMTYREVWZXJPLF-AFHUBHILSA-N butorphanol D-tartrate Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O.N1([C@@H]2CC3=CC=C(C=C3[C@@]3([C@]2(CCCC3)O)CC1)O)CC1CCC1 GMTYREVWZXJPLF-AFHUBHILSA-N 0.000 claims description 3
- 229960001590 butorphanol tartrate Drugs 0.000 claims description 3
- 229940046978 chlorpheniramine maleate Drugs 0.000 claims description 3
- OPXKTCUYRHXSBK-UHFFFAOYSA-N clenbuterol hydrochloride Chemical compound Cl.CC(C)(C)NCC(O)C1=CC(Cl)=C(N)C(Cl)=C1 OPXKTCUYRHXSBK-UHFFFAOYSA-N 0.000 claims description 3
- 229960001399 clenbuterol hydrochloride Drugs 0.000 claims description 3
- 229960002925 clonidine hydrochloride Drugs 0.000 claims description 3
- 229960000525 diphenhydramine hydrochloride Drugs 0.000 claims description 3
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- XWAIAVWHZJNZQQ-UHFFFAOYSA-N donepezil hydrochloride Chemical compound [H+].[Cl-].O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 XWAIAVWHZJNZQQ-UHFFFAOYSA-N 0.000 claims description 3
- 229960003135 donepezil hydrochloride Drugs 0.000 claims description 3
- OYFJQPXVCSSHAI-QFPUQLAESA-N enalapril maleate Chemical compound OC(=O)\C=C/C(O)=O.C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 OYFJQPXVCSSHAI-QFPUQLAESA-N 0.000 claims description 3
- 229960000309 enalapril maleate Drugs 0.000 claims description 3
- IVLVTNPOHDFFCJ-UHFFFAOYSA-N fentanyl citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 IVLVTNPOHDFFCJ-UHFFFAOYSA-N 0.000 claims description 3
- 229960004207 fentanyl citrate Drugs 0.000 claims description 3
- 229960003607 granisetron hydrochloride Drugs 0.000 claims description 3
- SCFQUKBBGYTJNC-UHFFFAOYSA-N heptyl prop-2-enoate Chemical compound CCCCCCCOC(=O)C=C SCFQUKBBGYTJNC-UHFFFAOYSA-N 0.000 claims description 3
- QYZRTBKYBJRGJB-UHFFFAOYSA-N hydron;1-methyl-n-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)indazole-3-carboxamide;chloride Chemical compound Cl.C1=CC=C2C(C(=O)NC3CC4CCCC(C3)N4C)=NN(C)C2=C1 QYZRTBKYBJRGJB-UHFFFAOYSA-N 0.000 claims description 3
- JUMYIBMBTDDLNG-OJERSXHUSA-N hydron;methyl (2r)-2-phenyl-2-[(2r)-piperidin-2-yl]acetate;chloride Chemical compound Cl.C([C@@H]1[C@H](C(=O)OC)C=2C=CC=CC=2)CCCN1 JUMYIBMBTDDLNG-OJERSXHUSA-N 0.000 claims description 3
- XZZXIYZZBJDEEP-UHFFFAOYSA-N imipramine hydrochloride Chemical compound [Cl-].C1CC2=CC=CC=C2N(CCC[NH+](C)C)C2=CC=CC=C21 XZZXIYZZBJDEEP-UHFFFAOYSA-N 0.000 claims description 3
- 229960002102 imipramine hydrochloride Drugs 0.000 claims description 3
- MOYKHGMNXAOIAT-JGWLITMVSA-N isosorbide dinitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O[N+](=O)[O-])CO[C@@H]21 MOYKHGMNXAOIAT-JGWLITMVSA-N 0.000 claims description 3
- 229960000201 isosorbide dinitrate Drugs 0.000 claims description 3
- YNQQEYBLVYAWNX-WLHGVMLRSA-N ketotifen fumarate Chemical compound OC(=O)\C=C\C(O)=O.C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 YNQQEYBLVYAWNX-WLHGVMLRSA-N 0.000 claims description 3
- 229960003630 ketotifen fumarate Drugs 0.000 claims description 3
- 229960004393 lidocaine hydrochloride Drugs 0.000 claims description 3
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 claims description 3
- NEKCRUIRPWNMLK-SCIYSFAVSA-N lurasidone hydrochloride Chemical compound Cl.C1=CC=C2C(N3CCN(CC3)C[C@@H]3CCCC[C@H]3CN3C(=O)[C@@H]4[C@H]5CC[C@H](C5)[C@@H]4C3=O)=NSC2=C1 NEKCRUIRPWNMLK-SCIYSFAVSA-N 0.000 claims description 3
- 229960002863 lurasidone hydrochloride Drugs 0.000 claims description 3
- LDDHMLJTFXJGPI-UHFFFAOYSA-N memantine hydrochloride Chemical compound Cl.C1C(C2)CC3(C)CC1(C)CC2(N)C3 LDDHMLJTFXJGPI-UHFFFAOYSA-N 0.000 claims description 3
- 229960000967 memantine hydrochloride Drugs 0.000 claims description 3
- LZULAZTXJLWELL-UHFFFAOYSA-N methyl hex-5-ynoate Chemical compound COC(=O)CCCC#C LZULAZTXJLWELL-UHFFFAOYSA-N 0.000 claims description 3
- 229960001033 methylphenidate hydrochloride Drugs 0.000 claims description 3
- 229960004715 morphine sulfate Drugs 0.000 claims description 3
- GRVOTVYEFDAHCL-RTSZDRIGSA-N morphine sulfate pentahydrate Chemical compound O.O.O.O.O.OS(O)(=O)=O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O GRVOTVYEFDAHCL-RTSZDRIGSA-N 0.000 claims description 3
- 229960000770 ondansetron hydrochloride Drugs 0.000 claims description 3
- 229960005434 oxybutynin Drugs 0.000 claims description 3
- 229960003617 oxycodone hydrochloride Drugs 0.000 claims description 3
- OLDRWYVIKMSFFB-SSPJITILSA-N palonosetron hydrochloride Chemical compound Cl.C1N(CC2)CCC2[C@@H]1N1C(=O)C(C=CC=C2CCC3)=C2[C@H]3C1 OLDRWYVIKMSFFB-SSPJITILSA-N 0.000 claims description 3
- 229960003359 palonosetron hydrochloride Drugs 0.000 claims description 3
- UWCVGPLTGZWHGS-ZORIOUSZSA-N pergolide mesylate Chemical compound CS(O)(=O)=O.C1=CC([C@H]2C[C@@H](CSC)CN([C@@H]2C2)CCC)=C3C2=CNC3=C1 UWCVGPLTGZWHGS-ZORIOUSZSA-N 0.000 claims description 3
- 229960001511 pergolide mesylate Drugs 0.000 claims description 3
- 229960001309 procaine hydrochloride Drugs 0.000 claims description 3
- 229960002789 procaterol hydrochloride Drugs 0.000 claims description 3
- 229960004604 propranolol hydrochloride Drugs 0.000 claims description 3
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol hydrochloride Natural products C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 claims description 3
- NTHPAPBPFQJABD-LLVKDONJSA-N ramosetron Chemical compound C12=CC=CC=C2N(C)C=C1C(=O)[C@H]1CC(NC=N2)=C2CC1 NTHPAPBPFQJABD-LLVKDONJSA-N 0.000 claims description 3
- 229950001588 ramosetron Drugs 0.000 claims description 3
- 229960002349 ropinirole hydrochloride Drugs 0.000 claims description 3
- 229960003198 tamsulosin hydrochloride Drugs 0.000 claims description 3
- CEIJFEGBUDEYSX-FZDBZEDMSA-N tandospirone Chemical compound O=C([C@@H]1[C@H]2CC[C@H](C2)[C@@H]1C1=O)N1CCCCN(CC1)CCN1C1=NC=CC=N1 CEIJFEGBUDEYSX-FZDBZEDMSA-N 0.000 claims description 3
- 229950000505 tandospirone Drugs 0.000 claims description 3
- 229960003553 tolterodine tartrate Drugs 0.000 claims description 3
- QDWJJTJNXAKQKD-UHFFFAOYSA-N trihexyphenidyl hydrochloride Chemical compound Cl.C1CCCCC1C(C=1C=CC=CC=1)(O)CCN1CCCCC1 QDWJJTJNXAKQKD-UHFFFAOYSA-N 0.000 claims description 3
- 229960004479 trihexyphenidyl hydrochloride Drugs 0.000 claims description 3
- 229960004846 tulobuterol hydrochloride Drugs 0.000 claims description 3
- RRLMGCBZYFFRED-UHFFFAOYSA-N undecyl prop-2-enoate Chemical compound CCCCCCCCCCCOC(=O)C=C RRLMGCBZYFFRED-UHFFFAOYSA-N 0.000 claims description 3
- 229960000881 verapamil hydrochloride Drugs 0.000 claims description 3
- AKUVRZKNLXYTJX-UHFFFAOYSA-N 3-benzylazetidine Chemical compound C=1C=CC=CC=1CC1CNC1 AKUVRZKNLXYTJX-UHFFFAOYSA-N 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- 229960001657 chlorpromazine hydrochloride Drugs 0.000 claims description 2
- 239000004808 2-ethylhexylester Substances 0.000 claims 1
- UAIXRPCCYXNJMQ-RZIPZOSSSA-N buprenorphine hydrochlorie Chemical compound [Cl-].C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)C[NH+]2CC1CC1 UAIXRPCCYXNJMQ-RZIPZOSSSA-N 0.000 claims 1
- 229940001468 citrate Drugs 0.000 claims 1
- 229940044231 diltia Drugs 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 180
- 238000012360 testing method Methods 0.000 description 53
- ZQMHJBXHRFJKOT-UHFFFAOYSA-N methyl 2-[(1-methoxy-2-methyl-1-oxopropan-2-yl)diazenyl]-2-methylpropanoate Chemical compound COC(=O)C(C)(C)N=NC(C)(C)C(=O)OC ZQMHJBXHRFJKOT-UHFFFAOYSA-N 0.000 description 52
- 239000007877 V-601 Substances 0.000 description 48
- 238000006243 chemical reaction Methods 0.000 description 47
- 229940079593 drug Drugs 0.000 description 40
- 230000000052 comparative effect Effects 0.000 description 34
- 239000002904 solvent Substances 0.000 description 34
- 238000002360 preparation method Methods 0.000 description 25
- 239000003505 polymerization initiator Substances 0.000 description 24
- 238000010992 reflux Methods 0.000 description 24
- 239000000654 additive Substances 0.000 description 22
- 238000000034 method Methods 0.000 description 22
- GOXQRTZXKQZDDN-UHFFFAOYSA-N 2-Ethylhexyl acrylate Chemical compound CCCCC(CC)COC(=O)C=C GOXQRTZXKQZDDN-UHFFFAOYSA-N 0.000 description 21
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 20
- CQEYYJKEWSMYFG-UHFFFAOYSA-N butyl acrylate Chemical compound CCCCOC(=O)C=C CQEYYJKEWSMYFG-UHFFFAOYSA-N 0.000 description 20
- 230000000996 additive effect Effects 0.000 description 17
- 125000003396 thiol group Chemical group [H]S* 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 238000009472 formulation Methods 0.000 description 15
- 239000012458 free base Substances 0.000 description 15
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- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 14
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 14
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 14
- JKNCOURZONDCGV-UHFFFAOYSA-N 2-(dimethylamino)ethyl 2-methylprop-2-enoate Chemical group CN(C)CCOC(=O)C(C)=C JKNCOURZONDCGV-UHFFFAOYSA-N 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- HCLJOFJIQIJXHS-UHFFFAOYSA-N 2-[2-[2-(2-prop-2-enoyloxyethoxy)ethoxy]ethoxy]ethyl prop-2-enoate Chemical compound C=CC(=O)OCCOCCOCCOCCOC(=O)C=C HCLJOFJIQIJXHS-UHFFFAOYSA-N 0.000 description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 230000000704 physical effect Effects 0.000 description 10
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 9
- 206010040880 Skin irritation Diseases 0.000 description 9
- 239000003522 acrylic cement Substances 0.000 description 9
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F293/00—Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
- C09J7/00—Adhesives in the form of films or foils
- C09J7/20—Adhesives in the form of films or foils characterised by their carriers
Landscapes
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Description
本発明は、支持体と粘着剤および塩基性薬物の塩を含有する粘着剤層とを備えた医療用貼付剤に関わり、詳細には、粘着剤としての粘着性ポリマーが、弱塩基性モノマーを共重合した星型アクリル系ブロックポリマーである医療用貼付剤に関するものである。 The present invention relates to a medical patch comprising a support and a pressure-sensitive adhesive layer containing a pressure-sensitive adhesive and a salt of a basic drug, in particular, a pressure-sensitive adhesive polymer as a pressure-sensitive adhesive, a weakly basic monomer The present invention relates to a medical patch which is a copolymerized star-shaped acrylic block polymer.
生体内へ薬物を投与して疾患治療または予防を行うための製剤として、腸管や肝臓等の初回通過効果による薬物代謝を回避でき、更に副作用が軽減でき、しかも薬物を長時間にわたって持続的に投与可能な貼付剤がある。その中でも、投与が容易で投与量を厳格に制御できることから、粘着剤中に薬物を含有させた経皮吸収製剤の開発が盛んに行われている。 As a preparation for treating or preventing disease by administering a drug to a living body, it can avoid drug metabolism due to the first-pass effect in the intestinal tract and liver, further reduce side effects, and continuously administer the drug for a long time There are possible patches. Above all, transdermal preparations containing a drug in an adhesive have been actively developed because of easy administration and strict control of the dose.
医療用貼付剤は、支持体、粘着剤を主成分とする粘着基剤と薬物を含有する粘着剤層(粘着剤組成物)、および剥離ライナーから構成され、使用時に剥離ライナーを取り除き、所定の場所に貼付する。製剤中の薬物を十分に皮膚透過させるために、医療用貼付剤は所定期間、皮膚に付着していなければならず、そのために十分な粘着性を有する必要がある。 The medical patch is composed of a support, a pressure-sensitive adhesive layer containing a pressure-sensitive adhesive as a main component and a drug (pressure-sensitive adhesive composition), and a release liner. Attach it to the place. In order for the drug in the preparation to sufficiently penetrate the skin, the medical patch must adhere to the skin for a predetermined period of time, and therefore must have sufficient tackiness.
医療用貼付剤に配合する薬物は、塩の形態を使用するよりも、遊離塩基を使用した方が高い経皮吸収性を示すことが知られているが、遊離塩基の状態では不安定な薬物も多く、一般的に流通している医療用薬物原薬も塩形態で供給される場合が多い。 Drugs used in medical patches are known to show higher transdermal absorbability when using the free base than when using the salt form, but drugs that are unstable in the free base state In general, drug substance for medical use that is generally distributed is often supplied in a salt form.
塩形態の薬物を使用する場合は、塩基性添加物を用いて、貼付剤中で遊離塩基に変換させる方法により、経皮吸収性を高める報告がみられる(特許文献1)。しかしながら、添加物の添加により、基剤の粘着物性や熱安定性などを低下させ、皮膚付着に必要な粘着性を確保できなくなる可能性がある。さらに、塩基性添加物と塩基性薬物の塩とが反応すると、遊離塩基とともに、塩基性の塩(塩基性塩)が生成されてくるが、塩基性塩の中には、貼付剤製造工程における中間生成物中、あるいは貼付剤中で結晶化し、生産効率の低下、さらには貼付剤物性の低下を招く恐れがある。また、塩基性塩にはそれ自体が皮膚刺激性を有する物質も多い。 When a salt-form drug is used, there is a report that transdermal absorbability is enhanced by a method of converting it to a free base in a patch using a basic additive (Patent Document 1). However, the addition of the additive may reduce the adhesive properties and thermal stability of the base, and may make it impossible to secure the adhesiveness necessary for adhesion to the skin. Further, when the basic additive reacts with the salt of the basic drug, a basic salt (basic salt) is generated together with the free base. It may crystallize in the intermediate product or in the patch, leading to a decrease in production efficiency and further to a decrease in physical properties of the patch. In addition, there are many basic salts which have skin irritation.
一方、特許文献2では、アミノ化したメタクリル酸共重合体を貼付剤中に配合することによって貼付剤中で塩基性薬物の塩の遊離塩基への変換を試みているが、この方法だと、貼付剤の粘着力が低下する。
On the other hand, in
さらに、特許文献3では、共重合成分としてアミノ基を有する(メタ)アクリルアミドを含有したアクリル粘着剤を使用した貼付剤が記載されているが、貼付剤の粘着物性の面で満足できるものではなく、優れた薬物放出性と貼付剤物性を兼ね備えた貼付剤が望まれていた。
Furthermore,
本発明は、上記従来の課題を解決するためになされたものであり、その1つの目的とするところは、星型(本明細書中、「星形」とも呼称する)アクリル系ブロックポリマーに存在する弱塩基性官能基により、貼付剤中において塩基性添加物を配合せずとも塩基性薬物の塩の遊離塩基への変換が可能であるため、高い薬効が期待でき、貼付物性を損なわず、かつ皮膚刺激性の低い貼付剤を提供することにある。 The present invention has been made to solve the above-mentioned conventional problems, and one object of the present invention is to provide a star-shaped (also referred to as “star-shaped”) acrylic block polymer. Due to the weakly basic functional group, it is possible to convert a salt of a basic drug into a free base without blending a basic additive in the patch, and high drug efficacy can be expected without impairing the patch properties. Another object of the present invention is to provide a patch having low skin irritation.
かかる課題を解決するべく、本発明者らは鋭意研究を重ねた結果、塩基性薬物の塩を含む医療用貼付剤において、粘着剤として弱塩基性モノマーを共重合した星型アクリル系ブロックポリマーを用いることで、高い薬効を示し、粘着基剤の粘着物性に影響を与えず、かつ皮膚刺激性の低い医療用貼付剤を提供できることを見出した。とりわけ、従来の星型アクリル系ブロックポリマーとは異なり、重合性モノマーとして弱塩基性モノマー含む共重合体構造を有する星型アクリル系ブロックポリマーを粘着性ポリマーとして使用することにより、薬物、とりわけ塩基性薬物を含有する貼付剤において、従来からの課題であった塩基性薬物を含有することによる貼付剤の物理的特性(例えば、粘着物性、保持特性など)を損なうことなく、その結果、長時間に渡り皮膚に貼り付け可能となり、且つ皮膚刺激性が低く、薬物放出性が高い優れた医療用の貼付剤を供することができることを初めて見出した。 In order to solve this problem, the present inventors have conducted intensive studies and found that, in a medical patch containing a salt of a basic drug, a star-shaped acrylic block polymer obtained by copolymerizing a weakly basic monomer as an adhesive was used. It has been found that by using such a medicated patch, it shows a high drug effect, does not affect the adhesive properties of the adhesive base, and has low skin irritation. In particular, unlike conventional star-shaped acrylic block polymers, by using a star-shaped acrylic block polymer having a copolymer structure containing a weakly basic monomer as a polymerizable monomer as an adhesive polymer, drugs, especially basic In a patch containing a drug, without impairing the physical properties (for example, adhesive properties, retention properties, etc.) of the patch by containing a basic drug, which has been a conventional problem, as a result, It has been found for the first time that it is possible to provide an excellent medical patch that can be stuck to migrating skin, has low skin irritation, and has a high drug release property.
すなわち、本発明の態様は、以下のとおりである。
星型アクリル系ブロックポリマー及びその製造方法
[1]少なくとも3本の鎖状ポリマー部分がメルカプト基の硫黄残基を中心にして放射状に延びている星型構造をとる星型アクリル系ブロックポリマーであって、該星型アクリル系ブロックポリマーの全構造単位の30〜99.9質量%が炭素数7〜17の(メタ)アクリル酸アルキルエステル構造単位であり、少なくとも1本の前記鎖状ポリマー部分が炭素数7〜17の(メタ)アクリル酸アルキルエステルと弱塩基性モノマーを含む重合性モノマーの共重合体構造を有する構造単位である星型アクリル系ブロックポリマー;
[1−1]前記該星型アクリル系ブロックポリマーの全構造単位の50〜99.9質量%が炭素数7〜17の(メタ)アクリル酸アルキルエステル構造単位である、上記[1]に記載の星型アクリル系ブロックポリマー。
[1−a]
塩基性薬物の塩および粘着剤を含む粘着剤組成物を含む医療用貼付剤であって、前記粘着剤が、少なくとも3本の鎖状ポリマー部分がメルカプト基を中心にして放射状に延びている星型構造を有し、前記ポリマー部分の全構造単位の50〜99.9質量%が炭素数7〜17の(メタ)アクリル酸アルキルエステル構造単位であり、少なくとも1本の前記鎖状ポリマー部分が炭素数7〜17の(メタ)アクリル酸アルキルエステルと弱塩基性モノマーを含む重合性モノマーの共重合体構造を有する星型アクリル系ブロックポリマーであることを特徴とする、医療用貼付剤。
[1−2]
重合性モノマーが、更に、その他の重合性モノマーおよび多官能性モノマーからなる群から選択される1種または2種以上の組み合わせを含んでいてもよい、上記[1]に記載の星型アクリル系ブロックポリマー。
[2]前記星形アクリル系ブロックポリマーの全構造単位に対する弱塩基性モノマーの含有量が0.1〜39質量%である、上記[1]に記載の星型アクリル系ブロックポリマー;
[3]鎖状ポリマー部分がラジカル重合性モノマーの重合体構造を含む、上記[1]または[2]のいずれかに記載の星型アクリル系ブロックポリマー。
[4]炭素数7〜17の(メタ)アクリル酸アルキルエステルが(メタ)アクリル酸ブチルエステル、(メタ)アクリル酸t−ブチルエステル、(メタ)アクリル酸ペンチルエステル、(メタ)アクリル酸ヘキシルエステル、(メタ)アクリル酸ヘプチルエステル、(メタ)アクリル酸オクチルエステル、(メタ)アクリル酸イソオクチルエステル、(メタ)アクリル酸ノニルエステル、(メタ)アクリル酸イソノニルエステル、(メタ)アクリル酸デシルエステル、(メタ)アクリル酸ウンデシルエステル、(メタ)アクリル酸ドデシルエステル、および(メタ)アクリル酸2−エチルヘキシルエステルからなる群から選択される1種または2種以上の組み合わせである、上記[1]〜[3]のいずれか1つに記載の星型アクリル系ブロックポリマー;
[5]弱塩基性モノマーが、第3級アミンが側鎖についた(メタ)アクリレート類、およびアミド類からなる群から選択される1種または2種以上の組み合わせである、上記[1]〜[4]のいずれか1つに記載の星型アクリル系ブロックポリマー;
[6]弱塩基性モノマーが(メタ)アクリル酸ジメチルアミノエチル、(メタ)アクリル酸ジエチルアミノエチル、(メタ)アクリル酸ジメチルアミノエチル四級アンモニウム塩、ジメチルアミノプロピルアクリルアミド、ジエチルアミノプロピルアクリルアミド、(メタ)アクリルアミド、N−メチル(メタ)アクリルアミド、およびN−プロピル(メタ)アクリルアミドからなる群から選択される1種または2種以上の組み合わせである、上記[1]〜[5]のいずれか1つに記載の星型アクリル系ブロックポリマー;
[7]上記[1]〜[6]のいずれか1つに記載の少なくとも3本の鎖状ポリマー部分がメルカプト基の硫黄残基を中心にして放射状に延びている星型アクリル系ブロックポリマーが、多価メルカプタンの存在下で重合性モノマーのラジカル重合を行う第1重合工程と、前記第1重合工程で得られた中間体ポリマーと重合性モノマーのラジカル重合を行う第2重合工程とを含み、前記第1重合工程および第2重合工程のうちの第2段階では、第1段階で得られたポリマー溶液に第2段階で用いる重合性モノマーを予め一括混合しておき、この混合溶液を用いて第2段階の重合を行い得られることを特徴とする、星形アクリル系ブロックポリマーの製造方法。That is, aspects of the present invention are as follows.
Star-shaped acrylic block polymer and method for producing the same [1] A star-shaped acrylic block polymer having a star-shaped structure in which at least three chain polymer portions extend radially around a sulfur residue of a mercapto group. 30 to 99.9% by mass of all the structural units of the star-shaped acrylic block polymer are (meth) acrylic acid alkyl ester structural units having 7 to 17 carbon atoms, and at least one of the chain polymer portions is A star-shaped acrylic block polymer that is a structural unit having a copolymer structure of a polymerizable monomer including a C7 to C17 alkyl (meth) acrylate and a weakly basic monomer;
[1-1] The above-mentioned [1], wherein 50 to 99.9% by mass of all the structural units of the star-shaped acrylic block polymer is a (meth) acrylic acid alkyl ester structural unit having 7 to 17 carbon atoms. Star-shaped acrylic block polymer.
[1-a]
What is claimed is: 1. A medical patch comprising a pressure-sensitive adhesive composition comprising a salt of a basic drug and a pressure-sensitive adhesive, wherein the pressure-sensitive adhesive comprises at least three linear polymer portions radially extending around a mercapto group. It has a type structure, and 50 to 99.9% by mass of all the structural units of the polymer portion is a (meth) acrylic acid alkyl ester structural unit having 7 to 17 carbon atoms, and at least one chain polymer portion has A medical patch characterized by being a star-shaped acrylic block polymer having a copolymer structure of an alkyl (meth) acrylate having 7 to 17 carbon atoms and a polymerizable monomer containing a weakly basic monomer.
[1-2]
The star-shaped acrylic system according to the above [1], wherein the polymerizable monomer may further include one or a combination of two or more selected from the group consisting of other polymerizable monomers and polyfunctional monomers. Block polymer.
[2] The star-shaped acrylic block polymer according to [1], wherein the content of the weakly basic monomer is 0.1 to 39% by mass based on all structural units of the star-shaped acrylic block polymer;
[3] The star-shaped acrylic block polymer according to any of the above [1] or [2], wherein the chain polymer portion contains a polymer structure of a radical polymerizable monomer.
[4] Alkyl (meth) acrylate having 7 to 17 carbon atoms is butyl (meth) acrylate, t-butyl (meth) acrylate, pentyl (meth) acrylate, hexyl (meth) acrylate , Heptyl (meth) acrylate, octyl (meth) acrylate, isooctyl (meth) acrylate, nonyl (meth) acrylate, isononyl (meth) acrylate, decyl (meth) acrylate [1] is one or a combination of two or more selected from the group consisting of undecyl (meth) acrylate, dodecyl (meth) acrylate, and 2-ethylhexyl (meth) acrylate -The star-shaped acrylic block according to any one of [3]. Polymers;
[5] The above [1] to [1], wherein the weakly basic monomer is one or a combination of two or more selected from the group consisting of (meth) acrylates having a tertiary amine attached to a side chain and amides. [4] The star-shaped acrylic block polymer according to any one of [4];
[6] The weakly basic monomer is dimethylaminoethyl (meth) acrylate, diethylaminoethyl (meth) acrylate, quaternary ammonium dimethylaminoethyl (meth) acrylate, dimethylaminopropylacrylamide, diethylaminopropylacrylamide, (meth) Any one of the above [1] to [5], which is one or a combination of two or more selected from the group consisting of acrylamide, N-methyl (meth) acrylamide, and N-propyl (meth) acrylamide The described star-shaped acrylic block polymer;
[7] The star-shaped acrylic block polymer according to any one of the above [1] to [6], wherein at least three chain polymer portions radially extend around a sulfur residue of a mercapto group. A first polymerization step of performing radical polymerization of a polymerizable monomer in the presence of a polyvalent mercaptan, and a second polymerization step of performing radical polymerization of the intermediate polymer and the polymerizable monomer obtained in the first polymerization step. In the second stage of the first polymerization step and the second polymerization step, the polymerizable monomer used in the second step is previously batch-mixed with the polymer solution obtained in the first step, and this mixed solution is used. And producing a star-shaped acrylic block polymer.
医療用貼付剤
[8]塩基性薬物の塩および粘着剤を含む粘着剤組成物を含む医療用貼付剤であって、前記粘着剤が、上記[1]〜[6]のいずれか1つに記載の少なくとも3本の鎖状ポリマー部分がメルカプト基の硫黄残基を中心にして放射状に延びている星型構造をとる星型アクリル系ブロックポリマーであって、該星型アクリル系ブロックポリマーの全構造単位の30〜99.9質量%が炭素数7〜17の(メタ)アクリル酸アルキルエステル構造単位であり、少なくとも1本の前記鎖状ポリマー部分が炭素数7〜17の(メタ)アクリル酸アルキルエステルと弱塩基性モノマーを含む重合性モノマーの共重合体構造を有する構造単位である星型アクリル系ブロックポリマーであることを特徴とする、医療用貼付剤;
[9]前記粘着剤の不揮発分に対する弱塩基性モノマーの含有量が0.1〜39質量%である、上記[8]に記載の医療用貼付剤;
[10]粘着剤組成物中の塩基性薬物の塩の含有量が0.1〜50質量%であり、粘着剤の含有量が50〜99.9質量%である、上記[8]または[9]に記載の医療用貼付剤
[11]炭素数7〜17の(メタ)アクリル酸アルキルエステルが(メタ)アクリル酸ブチルエステル、(メタ)アクリル酸t−ブチルエステル、(メタ)アクリル酸ペンチルエステル、(メタ)アクリル酸ヘキシルエステル、(メタ)アクリル酸ヘプチルエステル、(メタ)アクリル酸オクチルエステル、(メタ)アクリル酸イソオクチルエステル、(メタ)アクリル酸ノニルエステル、(メタ)アクリル酸イソノニルエステル、(メタ)アクリル酸デシルエステル、(メタ)アクリル酸ウンデシルエステル、(メタ)アクリル酸ドデシルエステル、および(メタ)アクリル酸2−エチルヘキシルエステルからなる群から選択される1種または2種以上の組み合わせである、上記[8]〜[10]のいずれか1つに記載されている医療用貼付剤;
[12]弱塩基性モノマーが(メタ)アクリル酸ジメチルアミノエチル、(メタ)アクリル酸ジエチルアミノエチル、(メタ)アクリル酸ジメチルアミノエチル四級アンモニウム塩、ジメチルアミノプロピルアクリルアミド、ジエチルアミノプロピルアクリルアミド、(メタ)アクリルアミド、N−メチル(メタ)アクリルアミド、およびN−プロピル(メタ)アクリルアミドからなる群から選択される1種または2種以上の組み合わせである、上記[8]〜[11]のいずれか1つに記載されている医療用貼付剤;
[13]塩基性薬物の塩がクエン酸フェンタニル、硫酸モルヒネ、塩酸オキシコドン、塩酸ブプレノルフィン、塩酸オキシブチニン、塩酸タムスロシン、酒石酸トルテロジン、メシル酸ラサギリン、メシル酸ペルゴリド、塩酸アマンタジン、塩酸トリヘキシフェニジル、塩酸ロピニロール、塩酸リドカイン、塩酸プロカイン、塩酸ドネペジル、塩酸メマンチン、クエン酸タンドスピロン、塩酸メチルフェニデート、塩酸ルラシドン、塩酸クロルプロマジン、塩酸イミプラミン、マレイン酸アセナピン、硫酸サルブタモール、塩酸クレンブテロール、塩酸ツロブテロール、塩酸プロカテロール、酒石酸ブトルファノール、クエン酸ペリソキサール、マレイン酸エナラプリル、塩酸プロプラノロール、塩酸ビソプロロール、塩酸クロニジン、塩酸ジルチアゼム、塩酸ベラパミル、硝酸イソソルビド、フマル酸ケトチフェン、マレイン酸クロルフェニラミン、塩酸アゼラスチン、塩酸ジフェンヒドラミン、塩酸グラニセトロン、塩酸ラモセトロン、塩酸パロノセトロン、および塩酸オンダンセトロンからなる群から選択される1種または2種以上の組み合わせである、上記[8]〜[12]のいずれかに記載されている医療用貼付剤。Medical patch [8] A medical patch comprising a pressure-sensitive adhesive composition containing a salt of a basic drug and a pressure-sensitive adhesive, wherein the pressure-sensitive adhesive is any one of the above-mentioned [1] to [6]. A star-shaped acrylic block polymer having a star-shaped structure in which at least three chain-shaped polymer portions extend radially around a sulfur residue of a mercapto group, wherein all of the star-shaped acrylic block polymers are 30 to 99.9% by mass of the structural unit is a (meth) acrylic acid alkyl ester structural unit having 7 to 17 carbon atoms, and at least one of the chain polymer portions is a (meth) acrylic acid having 7 to 17 carbon atoms. A medical patch characterized by being a star-shaped acrylic block polymer which is a structural unit having a copolymer structure of an alkyl ester and a polymerizable monomer containing a weakly basic monomer;
[9] The medical patch of the above-mentioned [8], wherein the content of the weakly basic monomer with respect to the nonvolatile content of the adhesive is 0.1 to 39% by mass;
[10] The above [8] or [8], wherein the content of the salt of the basic drug in the pressure-sensitive adhesive composition is 0.1 to 50% by mass, and the content of the pressure-sensitive adhesive is 50 to 99.9% by mass. 9] The medical patch according to [9], wherein the alkyl (meth) acrylate having 7 to 17 carbon atoms is butyl (meth) acrylate, t-butyl (meth) acrylate, pentyl (meth) acrylate. Ester, hexyl (meth) acrylate, heptyl (meth) acrylate, octyl (meth) acrylate, isooctyl (meth) acrylate, nonyl (meth) acrylate, isononyl (meth) acrylate Esters, decyl (meth) acrylate, undecyl (meth) acrylate, dodecyl (meth) acrylate, and ) Is one or more combinations selected from the group consisting of 2-ethylhexyl acrylate ester, the [8] to a medical patch as described in any one of [10];
[12] The weakly basic monomer is dimethylaminoethyl (meth) acrylate, diethylaminoethyl (meth) acrylate, quaternary ammonium salt of dimethylaminoethyl (meth) acrylate, dimethylaminopropylacrylamide, diethylaminopropylacrylamide, (meth) Any one of the above [8] to [11], which is one or a combination of two or more selected from the group consisting of acrylamide, N-methyl (meth) acrylamide, and N-propyl (meth) acrylamide Medical patches as described;
[13] The salt of the basic drug is fentanyl citrate, morphine sulfate, oxycodone hydrochloride, buprenorphine hydrochloride, oxybutynin hydrochloride, tamsulosin hydrochloride, tolterodine tartrate, rasagiline mesylate, pergolide mesylate, amantadine hydrochloride, trihexyphenidyl hydrochloride, ropinirole hydrochloride , Lidocaine hydrochloride, procaine hydrochloride, donepezil hydrochloride, memantine hydrochloride, tandospirone citrate, methylphenidate hydrochloride, lurasidone hydrochloride, chlorpromazine hydrochloride, imipramine hydrochloride, asenapine maleate, salbutamol sulfate, clenbuterol hydrochloride, tulobuterol hydrochloride, procaterol hydrochloride, butorphanol tartrate, Perisoxal citrate, enalapril maleate, propranolol hydrochloride, bisoprolol hydrochloride, clonidine hydrochloride, hydrochloric acid One or two selected from the group consisting of luthiazem, verapamil hydrochloride, isosorbide dinitrate, ketotifen fumarate, chlorpheniramine maleate, azelastine hydrochloride, diphenhydramine hydrochloride, granisetron hydrochloride, ramosetron hydrochloride, palonosetron hydrochloride, and ondansetron hydrochloride The medical patch according to any one of the above [8] to [12], which is a combination of the above.
本発明の別の態様は、以下の通りである。
[14]炭素数7〜17の(メタ)アクリル酸アルキルエステルがアクリル酸ブチルエステルおよびアクリル酸2−エチルヘキシルエステルからなる群から選択される1種または2種の組み合わせである、上記[8]〜[13]のいずれか1つに記載の医療用貼付剤;
[15]弱塩基性モノマーがメタクリル酸ジメチルアミノエチルまたはジメチルアミノプロピルアクリルアミドである、上記[8]〜[14]のいずれか1つに記載の医療用貼付剤;ならびに
[16]塩基性薬物の塩がメシル酸ラサギリンである、上記[8]〜[15]のいずれか1つに記載の医療用貼付剤。Another aspect of the present invention is as follows.
[14] The above-mentioned [8] to [8] to wherein the alkyl (meth) acrylate having 7 to 17 carbon atoms is one or a combination of two or more selected from the group consisting of butyl acrylate and 2-ethylhexyl acrylate. [13] The medical patch according to any one of [13];
[15] the medical patch according to any one of the above [8] to [14], wherein the weakly basic monomer is dimethylaminoethyl methacrylate or dimethylaminopropylacrylamide; The medical patch according to any one of the above [8] to [15], wherein the salt is rasagiline mesylate.
本発明のさらに別の態様は、以下の通りである。
[17]塩基性添加物を含まない、上記[8]〜[16]のいずれか1つに記載の医療用貼付剤;
[18]塩基性薬物の塩および粘着剤を含む粘着剤組成物を含む医療用貼付剤であって、前記粘着剤が上記[1]〜[6]のいずれか1つに記載の少なくとも3本の鎖状ポリマー部分がメルカプト基の硫黄残基を中心にして放射状に延びている星型構造をとる星型アクリル系ブロックポリマーであって、該星型アクリル系ブロックポリマーの全構造単位の30〜99.9質量%が炭素数7〜17の(メタ)アクリル酸アルキルエステル構造単位であり、少なくとも1本の前記鎖状ポリマー部分が炭素数7〜17の(メタ)アクリル酸アルキルエステルと弱塩基性モノマーを含む重合性モノマーの共重合体構造を有する構造単位である星型アクリル系ブロックポリマーであることを特徴とする、医療用貼付剤;
[19]星型アクリル系ブロックポリマーが、少なくとも3本の鎖状ポリマー部分がメルカプト基の硫黄残基を中心にして放射状に延びている星型アクリル系ブロックポリマーが、多価メルカプタンの存在下で重合性モノマーのラジカル重合を行う第1重合工程と、前記第1重合工程で得られた中間体ポリマーと重合性モノマーのラジカル重合を行う第2重合工程とを含み、前記第1重合工程および第2重合工程のうちの第2段階では、第1段階で得られたポリマー溶液に第2段階で用いる重合性モノマーを予め一括混合しておき、この混合溶液を用いて第2段階の重合を行うことを特徴とする、上記[7]〜[17]のいずれか1つに記載の医療用貼付剤;ならびに
[19](a)多価メルカプタンの存在下で、第1重合工程および第2重合工程からなるラジカル重合段階の各素段階で種類の同じかまたは異なる重合性モノマーを使用するラジカル重合を2段階で行うことにより星型アクリル系ブロックポリマーを製造する工程であって、前記2段階のうちの少なくとも一つの素段階で弱塩基性モノマーを使用し、前記2段階のうちの第2段階では、第1段階で得られたポリマー溶液と第2段階で用いる重合性モノマーの一部を重合させた後、第1段階で得られたポリマー溶液と第2段階で用いる重合性モノマーの残りを含むモノマー混合物を少しずつ添加混合して重合させる工程;および
(b)前記(a)で得られた星型アクリル系ブロックポリマーと塩基性薬物の塩を混合する工程
を含むことを特徴とする、上記[7]〜[18]のいずれか1つに記載の医療用貼付剤の製造方法。Still another embodiment of the present invention is as follows.
[17] The medical patch according to any one of the above [8] to [16], which does not contain a basic additive;
[18] A medical patch comprising a pressure-sensitive adhesive composition comprising a salt of a basic drug and a pressure-sensitive adhesive, wherein the pressure-sensitive adhesive comprises at least three pressure-sensitive adhesives according to any one of the above [1] to [6]. Is a star-shaped acrylic block polymer having a star-shaped structure in which the chain polymer portion radially extends around a sulfur residue of a mercapto group, and 30 to 30 of all structural units of the star-shaped acrylic block polymer. 99.9% by mass is a (meth) acrylic acid alkyl ester structural unit having 7 to 17 carbon atoms, and at least one of the chain polymer portions is a (meth) acrylic acid alkyl ester having 7 to 17 carbon atoms and a weak base. A medical patch, which is a star-shaped acrylic block polymer that is a structural unit having a copolymer structure of a polymerizable monomer containing a hydrophilic monomer;
[19] A star acrylic block polymer in which at least three chain polymer portions extend radially around a sulfur residue of a mercapto group in the presence of a polyvalent mercaptan A first polymerization step of performing a radical polymerization of a polymerizable monomer, and a second polymerization step of performing a radical polymerization of the intermediate polymer and the polymerizable monomer obtained in the first polymerization step, wherein the first polymerization step and the second polymerization step are performed. In the second stage of the two polymerization steps, the polymerizable monomer used in the second stage is previously mixed together with the polymer solution obtained in the first stage, and the second-stage polymerization is performed using the mixed solution. The medical patch according to any one of the above [7] to [17]; and [19] (a) a first polymerization step and a second polymerization step in the presence of a polyvalent mercaptan. A step of producing a star-shaped acrylic block polymer by performing two steps of radical polymerization using the same or different types of polymerizable monomers in each elementary step of the radical polymerization step comprising the steps, In at least one of the elementary steps, a weakly basic monomer is used, and in the second of the two steps, the polymer solution obtained in the first step and a part of the polymerizable monomer used in the second step are polymerized. (C) polymerizing the polymer solution obtained in the first step and the monomer mixture containing the remainder of the polymerizable monomer used in the second step by little by little; and (b) obtaining the polymer solution obtained in (a) above. Producing the medical patch according to any one of the above [7] to [18], comprising a step of mixing a salt of the star-shaped acrylic block polymer with a basic drug. Law.
本発明によれば、粘着剤として、弱塩基性モノマーを共重合した星型アクリル系ブロックポリマーを用いることによって、薬物、とりわけ塩基性薬物を含有する貼付剤において、塩基性添加物(例えばジエタノールアミン等のアミン類;酢酸ナトリウム等の塩基性の塩;ならびにアミノアルキルメタクリレートポリマー(EUDRAGIT E−100等)等の塩基性ポリマー)を添加せずとも製剤中で塩基性薬物の塩を高い効率で遊離塩基に変換でき、薬物放出性が高く、また粘着基剤の粘着物性、保持特性も低下せず、かつ皮膚刺激性の低い医療用貼付剤を提供できる。 According to the present invention, by using a star-shaped acrylic block copolymer obtained by copolymerizing a weakly basic monomer as an adhesive, a basic additive (for example, diethanolamine or the like) can be obtained in a patch containing a drug, especially a basic drug. Amines; basic salts such as sodium acetate; and basic polymers such as aminoalkyl methacrylate polymers (eg, EUDRAGIT E-100) without the addition of basic drug salts in the formulation with high efficiency. It is possible to provide a medical patch having a high drug release property, a low adhesive property and a low retention property of an adhesive base, and low skin irritation.
すなわち本発明が提供する医療用貼付剤により、薬物を、皮膚を介して循環血中に効率よく吸収させることができ、経口投与において見られる消化器系の副作用や、急激な血中濃度の上昇に伴って起こり得る副作用も回避できる。 That is, the medical patch provided by the present invention allows a drug to be efficiently absorbed into the circulating blood via the skin, and has a gastrointestinal side effect and a rapid increase in blood concentration seen in oral administration. Can also avoid the side effects that can occur with.
本発明の医療用貼付剤は、粘着性ポリマーとして作用する弱塩基性モノマーを共重合した星型アクリル系ブロックポリマーを粘着剤として用い、有効成分である塩基性薬物の塩を配合して得られる組成物(粘着剤組成物)を粘着剤層とし、これを支持体上に積層することにより調製される。 The medical patch of the present invention is obtained by using a star-shaped acrylic block polymer obtained by copolymerizing a weakly basic monomer acting as an adhesive polymer as an adhesive, and blending a salt of a basic drug as an active ingredient. It is prepared by using a composition (pressure-sensitive adhesive composition) as a pressure-sensitive adhesive layer and laminating it on a support.
上記星型アクリル系ブロックポリマー(星型アクリル系ブロックコポリマーとも称する)は、少なくとも3本の鎖状ポリマー部分がメルカプト基の硫黄残基を中心にして放射状に延びている星型構造を有する。かかる星型構造は、文献(例えば特許第2842782号明細書、特許第3385177号明細書、特許第4603398号明細書、特許第4744481号明細書、および特許第4916200号明細書等)においても知られている。本発明に係る星型アクリル系ブロックポリマーの構造の模式図(一例)を図1に示す。また、星型アクリル系ブロックポリマーは、該星型アクリル系ブロックポリマーの全構造単位の30〜99.9質量%が炭素数7〜17の(メタ)アクリル酸アルキルエステル構造単位である。該星型アクリル系ブロックポリマーの全構造単位中、炭素数7〜17の(メタ)アクリル酸アルキルエステル構造単位の含有割合は、好ましくは、60〜99.9質量%、35〜97質量%、より好ましくは70〜99.9質量%、40〜95質量%であり、一層好ましくは50〜85質量%である。該星型アクリル系ブロックポリマーの全構造単位中、炭素数7〜17の(メタ)アクリル酸アルキルエステル構造単位の含有割合が50質量%未満の場合、粘着性を十分に付与できない。なお、本明細書において、「(メタ)アクリル酸」は、アクリル酸またはメタクリル酸を意味し、ポリマー部分の「構造単位」は、ポリマーを構成する重合性モノマー由来の構造からなる単位を意味する。前記メルカプト基の硫黄残基の中心とは、言い換えれば該硫黄残基を有する多価メルカプタン由来の骨格のものを示す。
尚、本願明細書中、数値範囲を示す記載として、例えば「X〜Y質量%」であると記載する場合、特に断らない限り、「X質量%またはそれ以上からY質量%またはそれ以下」であることを意味する。The above-mentioned star-shaped acrylic block polymer (also referred to as a star-shaped acrylic block copolymer) has a star-shaped structure in which at least three chain polymer portions radially extend around a sulfur residue of a mercapto group. Such a star-shaped structure is also known in the literature (for example, Japanese Patent No. 2842782, Japanese Patent No. 3385177, Japanese Patent No. 4603398, Japanese Patent No. 4744481, and Japanese Patent No. 4916200). ing. FIG. 1 shows a schematic diagram (one example) of the structure of the star-shaped acrylic block polymer according to the present invention. In the star-shaped acrylic block polymer, 30 to 99.9% by mass of all structural units of the star-shaped acrylic block polymer is a (meth) acrylic acid alkyl ester structural unit having 7 to 17 carbon atoms. In all the structural units of the star-shaped acrylic block polymer, the content ratio of the alkyl (meth) acrylate having 7 to 17 carbon atoms is preferably 60 to 99.9% by mass, 35 to 97% by mass, It is more preferably 70 to 99.9% by mass and 40 to 95% by mass, and further preferably 50 to 85% by mass. When the content of the alkyl (meth) acrylate structural unit having 7 to 17 carbon atoms in all the structural units of the star-shaped acrylic block polymer is less than 50% by mass, sufficient tackiness cannot be imparted. In the present specification, “(meth) acrylic acid” means acrylic acid or methacrylic acid, and “structural unit” of a polymer portion means a unit having a structure derived from a polymerizable monomer constituting a polymer. . The center of the sulfur residue of the mercapto group means, in other words, a skeleton derived from a polyvalent mercaptan having the sulfur residue.
In the specification of the present application, when the numerical range is described as, for example, “X to Y mass%”, “X mass% or more to Y mass% or less” unless otherwise specified. It means there is.
炭素数7〜17の(メタ)アクリル酸アルキルエステル構造単位に対応する重合性モノマー(以下、「炭素数7〜17の(メタ)アクリル酸アルキルエステルモノマー」とも称する)、すなわち、炭素数7〜17の(メタ)アクリル酸アルキルエステルとしては、例えば、(メタ)アクリル酸ブチルエステル、(メタ)アクリル酸t−ブチルエステル、(メタ)アクリル酸ペンチルエステル、(メタ)アクリル酸ヘキシルエステル、(メタ)アクリル酸ヘプチルエステル、(メタ)アクリル酸オクチルエステル、(メタ)アクリル酸イソオクチルエステル、(メタ)アクリル酸ノニルエステル、(メタ)アクリル酸イソノニルエステル、(メタ)アクリル酸デシルエステル、(メタ)アクリル酸ウンデシルエステル、(メタ)アクリル酸ドデシルエステル、(メタ)アクリル酸2−エチルヘキシルエステル;などからなる群から選択される1種または2種以上の組み合わせが挙げられる。炭素数7〜17の(メタ)アクリル酸アルキルエステルモノマーの例としては、好ましくは(メタ)アクリル酸ブチルエステル、(メタ)アクリル酸t−ブチルエステル、および(メタ)アクリル酸2−エチルヘキシルエステル、(メタ)アクリル酸オクチルエステル、(メタ)アクリル酸イソオクチルエステル、(メタ)アクリル酸ノニルエステル、(メタ)アクリル酸イソノニルエステルが挙げられ、より好ましくは(メタ)アクリル酸ブチルエステルと(メタ)アクリル酸2−エチルヘキシルエステルの組み合わせが挙げられ、一層より好ましくはアクリル酸ブチルとアクリル酸2−エチルヘキシルエステルの組み合わせが挙げられる。ここで、炭素数7〜17の(メタ)アクリル酸アルキルエステルモノマーが、第1重合性モノマーおよび第2重合性モノマーとして使用される場合、同じであっても異なってもよい。 A polymerizable monomer corresponding to the alkyl (meth) acrylate structural unit having 7 to 17 carbon atoms (hereinafter also referred to as “alkyl (meth) acrylate monomer having 7 to 17 carbon atoms)”, that is, 7 to 17 carbon atoms; Examples of the alkyl (meth) acrylate 17 include butyl (meth) acrylate, t-butyl (meth) acrylate, pentyl (meth) acrylate, hexyl (meth) acrylate, and (meth) acrylate. ) Heptyl acrylate, octyl (meth) acrylate, isooctyl (meth) acrylate, nonyl (meth) acrylate, isononyl (meth) acrylate, decyl (meth) acrylate, (meth) ) Undecyl acrylate, dode (meth) acrylate Glycol ester, (meth) 2-ethylhexyl ester of acrylic acid; include one or more combinations selected from the group consisting of a. Examples of the alkyl (meth) acrylate having 7 to 17 carbon atoms preferably include butyl (meth) acrylate, t-butyl (meth) acrylate, and 2-ethylhexyl (meth) acrylate; Octyl (meth) acrylate, isooctyl (meth) acrylate, nonyl (meth) acrylate, isononyl (meth) acrylate, more preferably butyl (meth) acrylate and (meth) acrylate ) Combinations of 2-ethylhexyl acrylate and even more preferably combinations of butyl acrylate and 2-ethylhexyl acrylate. Here, when the alkyl (meth) acrylate monomer having 7 to 17 carbon atoms is used as the first polymerizable monomer and the second polymerizable monomer, they may be the same or different.
弱塩基性モノマーとは例えば、第3級アミンが側鎖についた(メタ)アクリレート類、およびアミド類からなる群から選択される1種または2種以上の組み合わせを意味する。弱塩基性モノマーとしては、例えば、(メタ)アクリル酸ジメチルアミノエチル、(メタ)アクリル酸ジエチルアミノエチルなどの(メタ)アクリル酸ジアルキルアミノアルキル類;(メタ)アクリル酸ジメチルアミノエチル四級アンモニウム塩などの(メタ)アクリル酸ジアルキルアミノアルキル四級アンモニウム塩類:ジメチルアミノプロピルアクリルアミド、ジエチルアミノプロピルアクリルアミド、(メタ)アクリルアミド、N−メチル(メタ)アクリルアミド、N−プロピル(メタ)アクリルアミドなどの(メタ)アクリルアミド類;などからなる群から選択される1種または2種以上の組み合わせが挙げられる。弱塩基性モノマーの例としては、好ましくは(メタ)アクリル酸ジアルキルアミノアルキル類、および(メタ)アミノアルキルアクリルアミド類、(メタ)アクリルアミド類が挙げられ、より好ましくは(メタ)アクリル酸ジメチルアミノエチル、(メタ)アクリル酸ジエチルアミノエチル、ジメチルアミノプロピルアクリルアミド、ジエチルアミノプロピルアクリルアミド、(メタ)アクリルアミド、N−メチル(メタ)アクリルアミド、N−プロピル(メタ)アクリルアミド、が挙げられ、一層より好ましくはメタクリル酸ジメチルアミノエチル、およびジメチルアミノプロピルアクリルアミドが挙げられる。ここで、弱塩基性モノマーが、第1重合性モノマーおよび第2重合性モノマーとして使用される場合、同じであっても異なってもよい。 The weakly basic monomer means, for example, one or a combination of two or more selected from the group consisting of (meth) acrylates having a tertiary amine attached to the side chain and amides. Examples of the weakly basic monomer include dialkylaminoalkyl (meth) acrylates such as dimethylaminoethyl (meth) acrylate and diethylaminoethyl (meth) acrylate; and quaternary ammonium salts of dimethylaminoethyl (meth) acrylate. (Meth) acrylic acid dialkylaminoalkyl quaternary ammonium salts: (meth) acrylamides such as dimethylaminopropylacrylamide, diethylaminopropylacrylamide, (meth) acrylamide, N-methyl (meth) acrylamide and N-propyl (meth) acrylamide One or a combination of two or more selected from the group consisting of: Examples of the weakly basic monomer include preferably dialkylaminoalkyl (meth) acrylates, (meth) aminoalkylacrylamides, and (meth) acrylamides, and more preferably dimethylaminoethyl (meth) acrylate. , Diethylaminoethyl (meth) acrylate, dimethylaminopropylacrylamide, diethylaminopropylacrylamide, (meth) acrylamide, N-methyl (meth) acrylamide, N-propyl (meth) acrylamide, and still more preferably dimethyl methacrylate. Aminoethyl, and dimethylaminopropylacrylamide. Here, when the weakly basic monomer is used as the first polymerizable monomer and the second polymerizable monomer, they may be the same or different.
上記の弱塩基性モノマーは、1種のみ用いてもよいし、2種以上を併用してもよい。上記星形アクリル系ブロックポリマーの全構造単位中、弱塩基性モノマーの含有割合は総計で、0.1〜39質量%、好ましくは1〜39質量%、より好ましくは1.5〜39質量%である。あるいは、弱塩基性モノマーの含有割合は総計で、星形アクリル系ブロックポリマーの全構造単位中、0.1〜39質量%、好ましくは1〜39質量%、より好ましくは1.5〜39質量%である。弱塩基性モノマーの含有割合が総計で0.1質量%未満の場合、塩基性薬物の塩の遊離塩基への変換作用が発現しない。一方、弱塩基性モノマーの含有割合が総計で39質量%を超えた場合、粘着性ポリマーとして物性バランスが崩れる。 One of the above weakly basic monomers may be used alone, or two or more may be used in combination. In all the structural units of the star-shaped acrylic block polymer, the content ratio of the weakly basic monomer is 0.1 to 39% by mass, preferably 1 to 39% by mass, and more preferably 1.5 to 39% by mass in total. It is. Alternatively, the content ratio of the weakly basic monomer is 0.1 to 39% by mass, preferably 1 to 39% by mass, more preferably 1.5 to 39% by mass in all structural units of the star-shaped acrylic block polymer. %. If the total content of the weakly basic monomer is less than 0.1% by mass, the effect of converting the salt of the basic drug into the free base is not exhibited. On the other hand, when the content ratio of the weakly basic monomer exceeds 39% by mass in total, the physical properties of the adhesive polymer are lost.
鎖状ポリマー部分がラジカル重合性モノマーの重合体構造を含み、ここで、ラジカル重合性モノマーは、例えば炭素数7〜17の(メタ)アクリル酸アルキルエステルモノマー、弱塩基性モノマー、その他の重合性モノマーである。
星型アクリル系ブロックポリマーが有する鎖状ポリマー部分は、弱塩基性モノマーに加えて、炭素数7〜17の(メタ)アクリル酸アルキルエステルおよび弱塩基性モノマー以外の重合性モノマー(以下、「その他の重合性モノマー」と称する)および/または下記の多官能性モノマー由来の構造単位を全構造単位の70、好ましくは50質量%未満の含有割合で含んでいてもよい。The chain polymer portion contains a polymer structure of a radical polymerizable monomer, wherein the radical polymerizable monomer is, for example, an alkyl (meth) acrylate monomer having 7 to 17 carbon atoms, a weakly basic monomer, or another polymerizable monomer. Monomer.
The chain polymer portion of the star-shaped acrylic block polymer includes, in addition to the weakly basic monomer, a polymerizable monomer other than the alkyl (meth) acrylate having 7 to 17 carbon atoms and the weakly basic monomer (hereinafter, “others”). And / or a structural unit derived from the following polyfunctional monomer at a content of 70, preferably less than 50% by mass of all the structural units.
その他の重合性モノマーとしては、ラジカル重合により単独重合または共重合が可能な重合性モノマーが挙げられ、例えば、(メタ)アクリル酸メチル、(メタ)アクリル酸エチルなどの炭素数6以下の(メタ)アクリル酸アルキルエステル;α−メチルスチレン、ビニルトルエン、スチレンなどのスチレン系モノマー;フェニルマレイミド、シクロヘキシルマレイミドなどのマレイミド系モノマー;メチルビニルエ−テル、エチルビニルエ−テル、イソブチルビニルエ−テルなどのビニルエ−テル系モノマー;フマル酸のモノアルキルエステル、フマル酸のジアルキルエステル;マレイン酸のモノアルキルエステル、マレイン酸のジアルキルエステル;イタコン酸のモノアルキルエステル、イタコン酸のジアルキルエステル;N−ビニル−2−ピロリドンなどのビニルピロリドン;メトキシトリエチレングリコールアクリレート、メトキシポリエチレングリコールメタクリレート、エトキシジエチレングリコールアクリレート、メトキシポリエチレングリコールアクリレートなどの(メタ)アクリル酸アルコキシポリアルキレングリコールエステル;(メタ)アクリロニトリル、ブタジエン、イソプレン、塩化ビニル、塩化ビニリデン、酢酸ビニル、ビニルケトン、ビニルピリジン、ビニルカルバゾ−ルなどのその他のビニル化合物;(メタ)アクリル酸、フマル酸、マレイン酸、イタコン酸などのカルボキシル基含有モノマー;などからなる群から選択される1種または2種以上の組み合わせが挙げられる。その他の重合性モノマーの例としては、好ましくは炭素数6以下の(メタ)アクリル酸アルキルエステル、およびビニル化合物が挙げられ、より好ましくは(メタ)アクリル酸メチル、(メタ)アクリル酸エチル、(メタ)アクリロニトリル、ブタジエン、イソプレン、塩化ビニル、塩化ビニリデン、酢酸ビニル、ビニルケトン、ビニルピリジン、ビニルカルバゾ−ルが挙げられ、一層より好ましくはメタクリル酸メチルまたは酢酸ビニルが挙げられる。ここで、その他の重合性モノマーが、第1重合性モノマーおよび第2重合性モノマーとして使用される場合、同じであっても異なってもよい。 Examples of other polymerizable monomers include polymerizable monomers that can be homopolymerized or copolymerized by radical polymerization, and include, for example, (meth) acrylates having 6 or less carbon atoms such as methyl (meth) acrylate and ethyl (meth) acrylate. A) alkyl esters of acrylic acid; styrene-based monomers such as α-methylstyrene, vinyltoluene and styrene; maleimide-based monomers such as phenylmaleimide and cyclohexylmaleimide; vinylethers such as methylvinylether, ethylvinylether and isobutylvinylether. Monoalkyl ester of fumaric acid, dialkyl ester of fumaric acid; monoalkyl ester of maleic acid, dialkyl ester of maleic acid; monoalkyl ester of itaconic acid, dialkyl ester of itaconic acid; N-vinyl- Vinylpyrrolidone such as pyrrolidone; (meth) acrylic acid alkoxypolyalkylene glycol esters such as methoxytriethylene glycol acrylate, methoxypolyethylene glycol methacrylate, ethoxydiethylene glycol acrylate and methoxypolyethylene glycol acrylate; And other vinyl compounds such as vinylidene chloride, vinyl acetate, vinyl ketone, vinyl pyridine and vinyl carbazole; and carboxyl group-containing monomers such as (meth) acrylic acid, fumaric acid, maleic acid and itaconic acid; and the like. One or a combination of two or more. Examples of other polymerizable monomers include preferably alkyl (meth) acrylates having 6 or less carbon atoms and vinyl compounds, more preferably methyl (meth) acrylate, ethyl (meth) acrylate, ( (Meth) acrylonitrile, butadiene, isoprene, vinyl chloride, vinylidene chloride, vinyl acetate, vinyl ketone, vinyl pyridine, vinyl carbazole, and even more preferably methyl methacrylate or vinyl acetate. Here, when other polymerizable monomers are used as the first polymerizable monomer and the second polymerizable monomer, they may be the same or different.
上記「その他の重合性モノマー」と組み合わせて、多官能性モノマーを含んでもよく、該多官能性モノマーとしては例えば、アルキレングリコールジ(メタ)アクリレート)アクリレート、エチレングリコ−ルジ(メタ)アクリレ−ト、テトラエチレングリコールジ(メタ)アクリレート、ポリエチレングリコ−ルジ(メタ)アクリレ−ト、プロピレングリコ−ルジ(メタ)アクリレ−ト、ポリプロピレングリコ−ル(メタ)アクリレ−ト、1,3−ブチレングリコ−ルジ(メタ)アクリレ−ト、1,6−ヘキサンジオ−ルジ(メタ)アクリレ−ト、ネオペンチルグリコ−ルジ(メタ)アクリレ−ト、2−ヒドロキシ1,3ジ(メタ)アクリロキシプロパン、2,2−ビス〔4−(アクリロキシエトキシ)フェニル〕プロパン、2,2−ビス〔4−(メタクリロキシエトキシ)フェニル〕プロパン、2,2−ビス〔4−(アクリロキシ・ポリエトキシ)フェニル〕プロパン、2,2−ビス〔4−(メタクリロキシ・ポリエトキシ)フェニル〕プロパン、2−ヒドロキシ−1−アクリロキシ−3−メタクリロキシプロパンなどのジオ−ルと(メタ)アクリル酸のジエステル化合物;トリメチロ−ルプロパントリ(メタ)アクリレ−ト、テトラメチロ−ルメタントリ(メタ)アクリレ−ト、テトラメチロ−ルメタンテトラ(メタ)アクリレ−ト、ペンタエリスリト−ルテトラキス(メタ)アクリレ−ト、ジペンタエリスリト−ルヘキサキス(メタ)アクリレ−トなどの1分子当たり3個以上の水酸基を有する化合物と(メタ)アクリル酸のポリエステル化合物;アリル(メタ)アクリレ−ト、ジビニルベンゼン;などからなる群から選択される1種または2種以上の組み合わせを挙げることができる。多官能性モノマーの例としては、好ましくはテトラエチレングリコールジ(メタ)アクリレートが挙げられ、より好ましくはテトラエチレングリコールジ(メタ)アクリレート、エチレングリコールジ(メタ)アクリレートが挙げられる。上記その他の重合性モノマー及び多官能性モノマーは、各々1種のみ用いてもよいし、各々もしくはあわせて2種以上を併用してもよい。 A polyfunctional monomer may be contained in combination with the above-mentioned "other polymerizable monomer". Examples of the polyfunctional monomer include alkylene glycol di (meth) acrylate) acrylate and ethylene glycol di (meth) acrylate. , Tetraethylene glycol di (meth) acrylate, polyethylene glycol di (meth) acrylate, propylene glycol di (meth) acrylate, polypropylene glycol (meth) acrylate, 1,3-butylene glycol L- (meth) acrylate, 1,6-hexanediol- (meth) acrylate, neopentylglycol-di (meth) acrylate, 2-hydroxy-1,3-di (meth) acryloxypropane, 2, 2-bis [4- (acryloxyethoxy) phenyl] propane, 2,2-bis 4- (methacryloxyethoxy) phenyl] propane, 2,2-bis [4- (acryloxypolyethoxy) phenyl] propane, 2,2-bis [4- (methacryloxypolyethoxy) phenyl] propane, 2-hydroxy-1 -Diester compounds of diol such as acryloxy-3-methacryloxypropane and (meth) acrylic acid; trimethylolpropanetri (meth) acrylate, tetramethylolmethanetri (meth) acrylate, tetramethylolmethanetetra (meth) acryle A compound having three or more hydroxyl groups per molecule such as pentaerythritol tetrakis (meth) acrylate, dipentaerythritol hexakis (meth) acrylate and a polyester compound of (meth) acrylic acid; Allyl (meth) acryle DOO, divinylbenzene; mention may be made of one or more combinations selected from the group consisting of a. Examples of the polyfunctional monomer preferably include tetraethylene glycol di (meth) acrylate, and more preferably include tetraethylene glycol di (meth) acrylate and ethylene glycol di (meth) acrylate. The other polymerizable monomers and polyfunctional monomers may be used alone or in combination of two or more.
本発明の星型アクリル系ブロックポリマーの典型的な1実施態様においては、
炭素数7〜17の(メタ)アクリル酸アルキルエステルが、(メタ)アクリル酸ブチルエステル、および(メタ)アクリル酸2−エチルヘキシルエステルからなる群から選択される1種または2種以上の組み合わせであり、そして
弱塩基性モノマーが、(メタ)アクリル酸ジアルキルアミノアルキル類、および(メタ)アクリルアミド類からなる群から選択される1種または2種以上の組み合わせである、
星型アクリル系ブロックポリマーが挙げられる。
ここで、少なくとも3本以上の鎖状ポリマー部分の内のある一本のポリマー部分を構成するラジカル重合性モノマーは、炭素数6以下の(メタ)アクリル酸アルキルエステル、およびビニル化合物からなる群から選択される1種または2種以上の組み合わせである。In a typical embodiment of the star acrylic block polymer of the present invention,
The alkyl (meth) acrylate having 7 to 17 carbon atoms is one or a combination of two or more selected from the group consisting of butyl (meth) acrylate and 2-ethylhexyl (meth) acrylate. And the weakly basic monomer is one or a combination of two or more selected from the group consisting of dialkylaminoalkyl (meth) acrylates and (meth) acrylamides,
Star-shaped acrylic block polymers can be used.
Here, the radical polymerizable monomer constituting one polymer part of at least three or more chain polymer parts is selected from the group consisting of alkyl (meth) acrylates having 6 or less carbon atoms and vinyl compounds. One or a combination of two or more selected.
本発明の星型アクリル系ブロックポリマーの典型的な1実施態様においては、
炭素数7〜17の(メタ)アクリル酸アルキルエステルが、アクリル酸ブチルとアクリル酸2−エチルヘキシルエステルの組み合わせであり、そして
弱塩基性モノマーが、メタクリル酸ジメチルアミノエチル、およびジメチルアミノプロピルアクリルアミドからなる群から選択される1種または2種以上の組み合わせである、
星型アクリル系ブロックポリマーが挙げられる。
ここで、少なくとも3本以上の鎖状ポリマー部分の内のある一本のポリマー部分を構成するラジカル重合性モノマーは、メタクリル酸メチルおよび酢酸ビニルからなる群から選択される1種または2種以上の組み合わせである。In a typical embodiment of the star acrylic block polymer of the present invention,
The alkyl (meth) acrylate having 7 to 17 carbon atoms is a combination of butyl acrylate and 2-ethylhexyl acrylate, and the weakly basic monomer is dimethylaminoethyl methacrylate and dimethylaminopropylacrylamide One or a combination of two or more selected from the group,
Star-shaped acrylic block polymers can be used.
Here, the radically polymerizable monomer constituting one polymer part of at least three or more chain polymer parts is one or two or more kinds selected from the group consisting of methyl methacrylate and vinyl acetate. Combination.
星型アクリル系ブロックポリマーは、その特徴的な星型アクリル系ブロックポリマー構造のためにミクロ層分離構造による物理的架橋が発現でき、架橋剤を使用しなくても粘着力と凝集力とのバランスを実現できる。 Due to its characteristic star-shaped acrylic block polymer structure, the star-shaped acrylic block polymer can exhibit physical cross-linking due to the micro-layer separation structure, and balances adhesion and cohesion without using a cross-linking agent. Can be realized.
以下、星型アクリル系ブロックポリマーを得るために特に適した製造方法について説明する。 Hereinafter, a production method particularly suitable for obtaining a star-shaped acrylic block polymer will be described.
星型アクリル系ブロックポリマーを得るために特に適した製造方法としては、多価メルカプタンを用いた多段階ラジカル重合方法において、反応系への全重合性モノマーの供給が完了した後に重合開始剤をさらに後添加する方法が挙げられる。このように後添加する重合開始剤を本発明では「ブースター」と称する。 As a production method particularly suitable for obtaining a star-shaped acrylic block polymer, in a multi-stage radical polymerization method using a polyvalent mercaptan, a polymerization initiator is further added after the supply of all polymerizable monomers to the reaction system is completed. Post-addition method may be mentioned. Such a polymerization initiator added later is referred to as a "booster" in the present invention.
多価メルカプタンの存在下で第1重合性モノマー(例えば、炭素数7〜17の(メタ)アクリル酸アルキルエステルモノマー、弱塩基性モノマー、もしくはその他の重合性モノマーのいずれか、またはこれらの混合物であり、好ましくはその他の重合性モノマー単独である)のラジカル重合を行うと、多価メルカプタンのメルカプト基の硫黄残基を発端として第1重合性モノマーがラジカル重合し、鎖状ポリマー部分がメルカプト基の硫黄残基(言い換えれば、該硫黄残基を持つ多価メルカプタン)を中心にして放射状に延びている第1星型構造を構成する。その際、多価メルカプタンのメルカプト基の硫黄残基の一部の原子価はこのラジカル重合の発端とならずに残る。そこで、さらに第2重合性モノマー(例えば、炭素数7〜17の(メタ)アクリル酸アルキルエステルモノマー、弱塩基性モノマー、その他の重合性モノマー、もしくは多官能性モノマーのいずれか、またはこれらの混合物であり、好ましくは炭素数7〜17の(メタ)アクリル酸アルキルエステルモノマー、弱塩基性モノマー、その他の重合性モノマー、および多官能性モノマーの混合物である)を加えてラジカル重合を行うと、多価メルカプタンの残ったメルカプト基の硫黄残基を発端として第2重合性モノマーがラジカル重合し、第1星型構造とは異なる第2星型構造を構成する。その結果、本願発明の星型アクリル系ブロックポリマーは、少なくとも3本の鎖状ポリマー部分を含む。 In the presence of a polyvalent mercaptan, a first polymerizable monomer (for example, any of C7 to C17 alkyl (meth) acrylate monomers, weakly basic monomers, or other polymerizable monomers, or a mixture thereof) And preferably other polymerizable monomer alone), the first polymerizable monomer undergoes radical polymerization starting from the sulfur residue of the mercapto group of the polyvalent mercaptan, and the chain polymer portion becomes a mercapto group. (In other words, a polyvalent mercaptan having the sulfur residue) constitutes a first star-shaped structure extending radially around the sulfur residue. At this time, the valence of a part of the sulfur residue of the mercapto group of the polyvalent mercaptan remains without being the starting point of the radical polymerization. Therefore, a second polymerizable monomer (for example, an alkyl (meth) acrylate monomer having 7 to 17 carbon atoms, a weakly basic monomer, another polymerizable monomer, or a polyfunctional monomer, or a mixture thereof) And preferably a mixture of an alkyl (meth) acrylate monomer having 7 to 17 carbon atoms, a weakly basic monomer, another polymerizable monomer, and a polyfunctional monomer) to perform radical polymerization. The second polymerizable monomer undergoes radical polymerization starting from the sulfur residue of the remaining mercapto group of the polyvalent mercaptan to form a second star structure different from the first star structure. As a result, the star-shaped acrylic block polymer of the present invention contains at least three chain polymer portions.
本発明の星型アクリル系ブロックポリマーの製造方法の典型的な1実施態様においては、
第1重合工程において、多価メルカプタンは、ジペンタエリスリトールヘキサキスチオグリコレート、およびジペンタエリスリトールヘキサキスチオプロピオネート(別名:ジペンタエリスリトール−β−メルカプトプロピオネート)(以下DPMPと略記)からなる群から選択される1種または2種以上の組み合わせであり、そしてラジカル重合性モノマーは、炭素数6以下の(メタ)アクリル酸アルキルエステル、およびビニル化合物からなる群から選択される1種または2種以上の組み合わせであるその他の重合性モノマーであり、
第2重合工程として、重合性モノマーが、(メタ)アクリル酸ブチルエステル、(メタ)アクリル酸t−ブチルエステルおよび(メタ)アクリル酸2−エチルヘキシルエステルからなる群から選択される1種または2種以上の組み合わせである炭素数7〜17の(メタ)アクリル酸アルキルエステル;(メタ)アクリル酸ジアルキルアミノアルキル類および(メタ)アクリルアミド類からなる群から選択される1種または2種以上の組み合わせである弱塩基性モノマー;炭素数6以下の(メタ)アクリル酸アルキルエステルおよびビニル化合物からなる群から選択される1種または2種以上の組み合わせであるその他の重合性モノマー;および、テトラエチレングリコールジ(メタ)アクリレートから選択される多官能性モノマーの混合物である。In a typical embodiment of the method for producing a star-shaped acrylic block polymer of the present invention,
In the first polymerization step, the polyvalent mercaptan is composed of dipentaerythritol hexakisthioglycolate and dipentaerythritol hexakisthiopropionate (also called dipentaerythritol-β-mercaptopropionate) (hereinafter abbreviated as DPMP). And the radical polymerizable monomer is one selected from the group consisting of alkyl (meth) acrylates having 6 or less carbon atoms and vinyl compounds. Or other polymerizable monomers that are a combination of two or more,
In the second polymerization step, the polymerizable monomer is one or two selected from the group consisting of butyl (meth) acrylate, t-butyl (meth) acrylate and 2-ethylhexyl (meth) acrylate One or more combinations selected from the group consisting of alkyl (meth) acrylates having 7 to 17 carbon atoms; dialkylaminoalkyl (meth) acrylates and (meth) acrylamides, which are the above combinations. A weakly basic monomer; another polymerizable monomer which is one or a combination of two or more selected from the group consisting of alkyl (meth) acrylates having 6 or less carbon atoms and a vinyl compound; and tetraethylene glycol di A mixture of polyfunctional monomers selected from (meth) acrylates That.
本発明の星型アクリル系ブロックポリマーの製造方法の典型的な1実施態様においては、
第1重合工程において、多価メルカプタンは、ジペンタエリスリトールヘキサキスチオプロピオネートあり、そしてラジカル重合性モノマーは、メタクリル酸メチルおよび酢酸ビニルからなる群から選択される1種または2種以上の組み合わせであるその他の重合性モノマーであり、
第2重合工程として、重合性モノマーが、アクリル酸ブチルとアクリル酸2−エチルヘキシルエステルからなる群から選択される1種または2種以上の組み合わせである炭素数7〜17の(メタ)アクリル酸アルキルエステル;メタクリル酸ジメチルアミノエチル、およびジメチルアミノプロピルアクリルアミドからなる群から選択される1種または2種以上の組み合わせである弱塩基性モノマー;メタクリル酸メチルおよび酢酸ビニルからなる群から選択される1種または2種以上の組み合わせからなる群から選択される1種または2種以上の組み合わせであるその他の重合性モノマー;および、テトラエチレングリコールジ(メタ)アクリレートから選択される多官能性モノマーの混合物である。In a typical embodiment of the method for producing a star-shaped acrylic block polymer of the present invention,
In the first polymerization step, the polyvalent mercaptan is dipentaerythritol hexakisthiopropionate, and the radically polymerizable monomer is one or a combination of two or more selected from the group consisting of methyl methacrylate and vinyl acetate. Other polymerizable monomers that are
In the second polymerization step, the polymerizable monomer is an alkyl (meth) acrylate having 7 to 17 carbon atoms, which is one or a combination of two or more selected from the group consisting of butyl acrylate and 2-ethylhexyl acrylate. Ester; weakly basic monomer which is one or a combination of two or more selected from the group consisting of dimethylaminoethyl methacrylate and dimethylaminopropylacrylamide; one selected from the group consisting of methyl methacrylate and vinyl acetate Or a mixture of one or more polymerizable monomers selected from the group consisting of two or more combinations; and a polyfunctional monomer selected from tetraethylene glycol di (meth) acrylate. is there.
星型アクリル系ブロックポリマーを得るためには、前記多段階ラジカル重合方法が2段階からなることが特に好適である。すなわち、多価メルカプタンの存在下で重合性モノマーのラジカル重合を行う第1重合工程と、前記第1重合工程で得られた中間体ポリマーと重合性モノマーのラジカル重合を行う第2重合工程とを含み、全重合性モノマーの全使用量の30〜99.9質量%が炭素数7以上の(メタ)アクリル酸アルキルエステルであり、反応系への全重合性モノマーの供給が完了した後にブースターをさらに後添加する製造方法が特に好適である。 In order to obtain a star-shaped acrylic block polymer, it is particularly preferable that the multi-stage radical polymerization method comprises two stages. That is, a first polymerization step of performing radical polymerization of a polymerizable monomer in the presence of a polyvalent mercaptan, and a second polymerization step of performing radical polymerization of the intermediate polymer and the polymerizable monomer obtained in the first polymerization step. 30 to 99.9% by mass of the total amount of the total polymerizable monomer used is a (meth) acrylic acid alkyl ester having 7 or more carbon atoms, and after the supply of the total polymerizable monomer to the reaction system is completed, the booster is activated. A production method in which further post-addition is performed is particularly preferable.
第2重合工程では、第1重合工程で得られたポリマー溶液に第2重合工程で使用する重合性モノマーを混合して重合を行う。 In the second polymerization step, polymerization is performed by mixing the polymerizable monomer used in the second polymerization step with the polymer solution obtained in the first polymerization step.
第2重合工程では、第1重合工程で得られたポリマー溶液と第2重合工程で使用する重合性モノマーを一括混合して重合してもよいし、第1重合工程で得られたポリマー溶液に第2重合工程で使用する重合性モノマーを少しずつ添加混合してもよい。 In the second polymerization step, the polymer solution obtained in the first polymerization step and the polymerizable monomer used in the second polymerization step may be mixed and polymerized at one time, or the polymer solution obtained in the first polymerization step may be mixed. The polymerizable monomer used in the second polymerization step may be added and mixed little by little.
特に好ましい第2重合工程の形態としては、(1a)第1重合工程で得られたポリマー溶液と(1b)第2重合工程で使用する重合性モノマーの一部とを必須に含む初期仕込み混合物(1)に重合開始剤を加えて重合を開始した後に、(2a)第1重合工程で得られたポリマー溶液と(2b)第2重合工程で使用する重合性モノマーの残りとを必須に含むモノマー混合物(2)および重合開始剤を少しずつ添加混合(好ましくは滴下混合)し、添加混合が終了した後(すなわち、反応系への全重合性モノマーの供給が完了した後)に、ブースターをさらに後添加する形態である。この方法であれば、第1重合工程で得られたポリマー溶液と第2重合工程で使用する重合性モノマーとが十分に均一混合できる。 As a particularly preferred form of the second polymerization step, (1a) the initially charged mixture essentially containing the polymer solution obtained in the first polymerization step and (1b) a part of the polymerizable monomer used in the second polymerization step ( After the polymerization is started by adding a polymerization initiator to 1), a monomer essentially containing (2a) the polymer solution obtained in the first polymerization step and (2b) the rest of the polymerizable monomer used in the second polymerization step The mixture (2) and the polymerization initiator are added little by little (preferably, drop-mixing), and after the addition and mixing are completed (that is, after the supply of all the polymerizable monomers to the reaction system is completed), the booster is further added. It is a form to be added later. According to this method, the polymer solution obtained in the first polymerization step and the polymerizable monomer used in the second polymerization step can be sufficiently uniformly mixed.
初期仕込み混合物(1)に重合開始剤を加えて重合を開始した後に、モノマー混合物(2)および重合開始剤を少しずつ添加混合して重合する場合、その添加混合は滴下によることが好ましく、滴下時間は、好ましくは20〜300分間、より好ましくは40〜200分間、さらに好ましくは60〜120分間である。添加混合を行う際の反応系の温度は、30〜200℃が好ましく、50〜150℃がより好ましい。 When the polymerization is started by adding the polymerization initiator to the initially charged mixture (1) and then gradually adding and mixing the monomer mixture (2) and the polymerization initiator, the addition and mixing are preferably performed by dropping, The time is preferably from 20 to 300 minutes, more preferably from 40 to 200 minutes, even more preferably from 60 to 120 minutes. The temperature of the reaction system at the time of adding and mixing is preferably from 30 to 200 ° C, more preferably from 50 to 150 ° C.
第1重合工程で得られたポリマー溶液(上記(1a)と(2a))は、第2重合工程で用いる際には重合が停止していることが好ましく、その時の重合性モノマーの重合率は総計で、好ましくは50〜90%、より好ましくは55〜85%、さらに好ましくは60〜80%である。重合を停止させる方法としては、例えば、第1重合工程で得られたポリマー溶液に重合禁止剤を添加する方法やポリマー溶液の温度を下げる方法等を挙げることができる。 When the polymer solution ((1a) and (2a)) obtained in the first polymerization step is used in the second polymerization step, the polymerization is preferably stopped, and the polymerization rate of the polymerizable monomer at that time is preferably In total, it is preferably 50 to 90%, more preferably 55 to 85%, and still more preferably 60 to 80%. Examples of the method for stopping the polymerization include a method of adding a polymerization inhibitor to the polymer solution obtained in the first polymerization step, a method of lowering the temperature of the polymer solution, and the like.
重合を停止させるために用いることができる重合禁止剤としては、例えば、ハイドロキノン、ハイドロキノンモノメチルエーテル、2,5−ビス(1,1,3,3−テトラメチルブチル)ハイドロキノン、2,5−ビス(1,1−ジメチルブチル)ハイドロキノン、メトキシフェノール、6−ターシャリーブチル−2,4−キシレノール、3,5−ジターシャリーブチルカテコールなどのフェノール類;N−ニトロソフェニルヒドロキシルアミンアルミニウム塩;フェノチアジン;などを挙げることができ、これらの1種のみ用いてもよいし、2種以上を併用してもよい。重合禁止剤の例としては、好ましくはフェノール類が挙げられ、より好ましくはハイドロキノンモノメチルエーテルが挙げられる。その全使用量は、第1重合工程で用いた重合性モノマーに対して、好ましくは1〜10000ppm、より好ましくは10〜1000ppm、さらに好ましくは20〜200ppmである。重合禁止剤の全使用量が1ppmよりも少ない場合は重合を効率的に停止させることができないおそれがある。一方、全使用量が10000ppmよりも過剰であると、第2重合工程の重合が開始しなくなるおそれがある。 Examples of the polymerization inhibitor that can be used for terminating the polymerization include hydroquinone, hydroquinone monomethyl ether, 2,5-bis (1,1,3,3-tetramethylbutyl) hydroquinone, and 2,5-bis ( Phenols such as 1,1-dimethylbutyl) hydroquinone, methoxyphenol, 6-tert-butyl-2,4-xylenol and 3,5-ditert-butylcatechol; N-nitrosophenylhydroxylamine aluminum salt; phenothiazine; One of these may be used alone, or two or more thereof may be used in combination. Examples of the polymerization inhibitor preferably include phenols, and more preferably include hydroquinone monomethyl ether. The total amount thereof is preferably 1 to 10000 ppm, more preferably 10 to 1000 ppm, and still more preferably 20 to 200 ppm, based on the polymerizable monomer used in the first polymerization step. When the total amount of the polymerization inhibitor is less than 1 ppm, the polymerization may not be efficiently stopped. On the other hand, if the total amount is more than 10,000 ppm, the polymerization in the second polymerization step may not start.
第1重合工程の重合は、ポリマー溶液の温度を40℃以下に下げれば、実質的に停止させることが可能である。重合開始剤の分解速度は温度に依存しているので、ポリマー溶液の温度が40℃以下になればラジカルがほとんど発生しないからである。重合の停止をより確実にするためには、ポリマー溶液の温度を20℃以下に下げればよい。 The polymerization in the first polymerization step can be substantially stopped by lowering the temperature of the polymer solution to 40 ° C. or lower. This is because the decomposition rate of the polymerization initiator depends on the temperature, and thus, when the temperature of the polymer solution becomes 40 ° C. or lower, almost no radicals are generated. In order to more reliably stop the polymerization, the temperature of the polymer solution may be reduced to 20 ° C. or less.
以下において、星型アクリル系ブロックポリマーを製造するために好適な方法に用いる原料を詳しく述べる。 Hereinafter, raw materials used in a method suitable for producing the star-shaped acrylic block polymer will be described in detail.
本発明で用いることができる重合性モノマーは、その全使用量中の30〜99.9質量%(典型的には、50〜99.9質量%)が炭素数7〜17の(メタ)アクリル酸アルキルエステルである。全重合性モノマー中の炭素数7〜17の(メタ)アクリル酸アルキルエステルの含有割合は総計で、好ましくは、60〜99.9質量%、35〜97.0質量%、より好ましくは70〜99.9質量%、40〜95.0質量%、さらに好ましくは80〜99.9質量%、42〜90.0質量%、特に好ましくは90〜99.9質量%、50〜86質量%である。全重合性モノマー中の炭素数7〜17の(メタ)アクリル酸アルキルエステルの含有割合が総計で50質量%未満(典型的には、30質量%未満)の場合、粘着性を十分に付与できない。 The polymerizable monomer that can be used in the present invention is such that 30 to 99.9% by mass (typically, 50 to 99.9% by mass) of the total amount thereof is (meth) acrylic having 7 to 17 carbon atoms. Acid alkyl esters. The content of the alkyl (meth) acrylate having 7 to 17 carbon atoms in the total polymerizable monomer is preferably 60 to 99.9% by mass, 35 to 97.0% by mass, more preferably 70 to 9% by mass. 99.9% by mass, 40 to 95.0% by mass, more preferably 80 to 99.9% by mass, 42 to 90.0% by mass, particularly preferably 90 to 99.9% by mass and 50 to 86% by mass. is there. When the content of the alkyl (meth) acrylate having 7 to 17 carbon atoms in the total polymerizable monomer is less than 50% by mass in total (typically less than 30% by mass), sufficient tackiness cannot be imparted. .
炭素数7〜17の(メタ)アクリル酸アルキルエステルの好ましい具体例は前述した通りであり、これらは1種のみ用いてもよいし、2種以上を併用してもよい。炭素数7〜17の(メタ)アクリル酸アルキルエステルは、多段階ラジカル重合工程のいずれの工程で用いられてもよいが、好ましくは、第2重合工程(3段階以上の重合工程を含む場合には最後の重合工程)で用いられる。 Preferred specific examples of the alkyl (meth) acrylate having 7 to 17 carbon atoms are as described above, and these may be used alone or in combination of two or more. The alkyl (meth) acrylate having 7 to 17 carbon atoms may be used in any of the multi-stage radical polymerization steps, but is preferably used in the second polymerization step (when three or more polymerization steps are included). Is used in the last polymerization step).
本発明で用いることができる重合性モノマーは、炭素数7〜17の(メタ)アクリル酸アルキルエステル以外の重合性モノマー(弱塩基性モノマーおよびその他の重合性モノマー)を全使用量中の70質量%未満(典型的には、50質量%未満)の含有割合で含んでいてもよい。 The polymerizable monomer that can be used in the present invention is a polymerizable monomer (weakly basic monomer and other polymerizable monomers) other than the alkyl (meth) acrylate having 7 to 17 carbon atoms, which accounts for 70% of the total amount used. % (Typically less than 50% by mass).
弱塩基性モノマーの好ましい具体例は前述した通りであり、これらは1種のみ用いてもよいし、2種以上を併用してもよい。弱塩基性モノマーは、多段階ラジカル重合工程のいずれの工程で用いられてもよいが、好ましくは、第2重合工程(3段階以上の重合工程を含む場合には最後の重合工程)で用いられる。 Preferred specific examples of the weakly basic monomer are as described above, and these may be used alone or in combination of two or more. The weakly basic monomer may be used in any of the multi-stage radical polymerization steps, but is preferably used in the second polymerization step (the last polymerization step in the case of including three or more polymerization steps). .
本発明で用いることができる弱塩基性モノマーの全重合性モノマー中の含有割合は、0.1〜39質量%、好ましくは、1〜39質量%(典型的には、1〜35質量%)、より好ましくは1.5〜39質量%(典型的には、1.5〜32質量%)である。 The content ratio of the weakly basic monomer that can be used in the present invention to the entire polymerizable monomer is 0.1 to 39% by mass, preferably 1 to 39% by mass (typically 1 to 35% by mass). , More preferably 1.5 to 39% by mass (typically 1.5 to 32% by mass).
また、弱塩基性モノマーの含有割合は総計で、前記星形アクリル系ブロックポリマーの全構造単位に対して0.1〜39質量%、好ましくは1〜39質量%(典型的には、1〜35質量%)、より好ましくは1.5〜39質量%(典型的には、1.5〜32質量%)である。弱塩基性モノマーの含有割合が総計で0.1質量%未満の場合、塩基性薬物の塩の遊離塩基への変換作用が発現しない。一方、弱塩基性モノマーの含有割合が総計で39質量%を超えた場合、粘着性ポリマーとして物性バランスが崩れる。 Further, the content ratio of the weakly basic monomer is 0.1 to 39% by mass, preferably 1 to 39% by mass (typically 1 to 39% by mass) based on the total structural units of the star-shaped acrylic block polymer. 35% by mass), more preferably 1.5 to 39% by mass (typically 1.5 to 32% by mass). If the total content of the weakly basic monomer is less than 0.1% by mass, the effect of converting the salt of the basic drug into the free base is not exhibited. On the other hand, when the content ratio of the weakly basic monomer exceeds 39% by mass in total, the physical properties of the adhesive polymer are lost.
その他の重合性モノマーとしては、ラジカル重合により単独重合または共重合が可能な重合性モノマーが挙げられ、好ましい具体例は前述した通りであり、これらは1種のみ用いてもよいし、2種以上を併用してもよい。その他の重合性モノマーは、多段階ラジカル重合工程のいずれの工程で用いられてもよいが、好ましくは、第1および第2重合工程(3段階以上の重合工程を含む場合には全重合工程)で用いられる。 Examples of other polymerizable monomers include polymerizable monomers that can be homopolymerized or copolymerized by radical polymerization, and preferred specific examples are as described above. These may be used alone or in combination of two or more. May be used in combination. Other polymerizable monomers may be used in any of the multi-stage radical polymerization steps, but preferably, the first and second polymerization steps (in the case of including three or more polymerization steps, the whole polymerization step) Used in
星型アクリル系ブロックポリマーを製造するために好適な方法では、多価メルカプタンの存在下でのラジカル重合を2段階以上の多段階で行うが、各素段階では種類の異なる重合性モノマーを使用することが好ましい。ここに、種類の異なる重合性モノマーとは、化学的構造の違う重合性モノマーを意味するのみでなく、同一化学構造の重合性モノマーの組合せにおいて配合割合の異なる場合をも意味する。各素段階で種類の異なる重合性モノマーを使用する例としては、例えば、メタクリル酸メチル90質量部およびアクリル酸ブチル10質量部からなる第1重合工程で使用する重合性モノマーの組合せに対して、メタクリル酸メチル10質量部およびアクリル酸ブチル90質量部からなる第2重合工程で使用する重合性モノマーの組合せを挙げることができる。この場合、得られる星型アクリル系ブロックポリマーがガラス転移温度(Tg)の大きく異なる鎖状ポリマー部分を有することになるので、本発明の効果を十分に発揮することができ、実用上の性能が高くなる。 In a method suitable for producing a star-shaped acrylic block polymer, radical polymerization in the presence of a polyvalent mercaptan is performed in two or more stages, but in each elementary stage, a different type of polymerizable monomer is used. Is preferred. Here, the different types of polymerizable monomers mean not only polymerizable monomers having different chemical structures but also different combinations of polymerizable monomers having the same chemical structure. Examples of using different types of polymerizable monomers in each elementary stage, for example, for the combination of polymerizable monomers used in the first polymerization step consisting of 90 parts by weight of methyl methacrylate and 10 parts by weight of butyl acrylate, Combinations of polymerizable monomers used in the second polymerization step consisting of 10 parts by mass of methyl methacrylate and 90 parts by mass of butyl acrylate can be mentioned. In this case, the obtained star-shaped acrylic block polymer has chain polymer portions having greatly different glass transition temperatures (Tg), so that the effects of the present invention can be sufficiently exerted, and practical performance can be reduced. Get higher.
上記方法で用いることができる多価メルカプタンとしては、例えば、エチレングリコールジチオグリコレート、エチレングリコールジチオプロピオネート、1,4−ブタンジオールジチオグリコレート、1,4−ブタンジオールジチオプロピオネートなどエチレングリコールや1,4−ブタンジオールのようなジオールとカルボキシル基含有メルカプタン類のジエステル;トリメチロールプロパントリチオグリコレート、トリメチロールプロパントリチオプロピオネートなどトリメチロールプロパンのようなトリオールとカルボキシル基含有メルカプタン類のトリエステル;ペンタエリスリトールテトラキスチオグリコレート、ペンタエリスリトールテトラキスチオプロピオネートなどペンタエリスリトールのような水酸基を4個有する化合物とカルボキシル基含有メルカプタン類のポリエステル;ジペンタエリスリトールヘキサキスチオグリコレート、ジペンタエリスリトールヘキサキスチオプロピオネート(別名:ジペンタエリスリトール−β−メルカプトプロピオネート)(以下DPMPと略記)などジペンタエリスリトールのような水酸基を6個有する化合物とカルボキシル基含有メルカプタン類のポリエステル化合物;その他水酸基を3個以上有する化合物とカルボキシル基含有メルカプタン類のポリエステル化合物;トリチオグリセリンなどのメルカプト基を3個以上有する化合物;2−ジ−n−ブチルアミノ−4,6−ジメルカプト−S−トリアジン、2,4,6−トリメルカプト−S−トリアジンなどのトリアジン多価チオール類;多価エポキシ化合物の複数のエポキシ基に硫化水素を付加させて複数のメルカプト基を導入してなる化合物;多価カルボン酸の複数のカルボキシル基とメルカプトエタノールをエステル化してなるエステル化合物;などを挙げることができ、これらの1種のみ用いてもよいし、2種以上を併用してもよい。多価メルカプタンは3価以上のメルカプタンが好ましく、多価メルカプタンの例としては、好ましくはジペンタエリスリトールのような水酸基を6個有する化合物、ペンタエリスリトールのような水酸基を4個有する化合物とカルボキシル基含有メルカプタン類のポリエステル化合物が挙げられ、より好ましくはジペンタエリスリトールヘキサキスチオグリコレート、ジペンタエリスリトールヘキサキスチオプロピオネート(別名:ジペンタエリスリトール−β−メルカプトプロピオネート)(以下DPMPと略記)、ペンタエリスリトールテトラキスチオグリコレート、ペンタエリスリトールテトラキスチオプロピオネートが挙げられ、より好ましくはジペンタエリスリトールヘキサキスチオプロピオネートが挙げられる。ここで、カルボキシル基含有メルカプタン類とは、チオグリコール酸、メルカプトプロピオン酸、チオサリチル酸などの1個のメルカプト基と1個のカルボキシル基を有する化合物を言う。 Examples of the polyvalent mercaptan that can be used in the above method include ethylene glycol dithioglycolate, ethylene glycol dithiopropionate, 1,4-butanediol dithioglycolate, and 1,4-butanediol dithiopropionate. Diesters of diols such as glycol and 1,4-butanediol with carboxyl-containing mercaptans; triols such as trimethylolpropane such as trimethylolpropane trithioglycolate and trimethylolpropane trithiopropionate; and carboxyl-containing mercaptans Triesters of the class: compounds having four hydroxyl groups such as pentaerythritol such as pentaerythritol tetrakisthioglycolate and pentaerythritol tetrakisthiopropionate And polyesters of carboxyl-containing mercaptans; dipentaerythritol hexakisthioglycolate, dipentaerythritol hexakisthiopropionate (also called dipentaerythritol-β-mercaptopropionate) (hereinafter abbreviated as DPMP) Compounds having 6 hydroxyl groups such as erythritol and polyester compounds of mercaptans containing carboxyl groups; other compounds having 3 or more hydroxyl groups and polyester compounds of mercaptans containing carboxyl groups; having 3 or more mercapto groups such as trithioglycerin Compounds; Triazine polyvalent thiols such as 2-di-n-butylamino-4,6-dimercapto-S-triazine and 2,4,6-trimercapto-S-triazine; A compound obtained by adding hydrogen sulfide to an xy group to introduce a plurality of mercapto groups; an ester compound obtained by esterifying a plurality of carboxyl groups of a polycarboxylic acid with mercaptoethanol; Only one kind may be used, or two or more kinds may be used in combination. The polyvalent mercaptan is preferably a mercaptan having three or more valences. Examples of the polyvalent mercaptan are preferably a compound having six hydroxyl groups such as dipentaerythritol, a compound having four hydroxyl groups such as pentaerythritol and a carboxyl group-containing compound. Examples thereof include polyester compounds of mercaptans, more preferably dipentaerythritol hexakisthioglycolate and dipentaerythritol hexakisthiopropionate (alias: dipentaerythritol-β-mercaptopropionate) (hereinafter abbreviated as DPMP). And pentaerythritol tetrakisthioglycolate and pentaerythritol tetrakisthiopropionate, and more preferably dipentaerythritol hexakisthiopropionate. Here, the carboxyl group-containing mercaptans refer to compounds having one mercapto group and one carboxyl group such as thioglycolic acid, mercaptopropionic acid, and thiosalicylic acid.
ラジカル重合を行う際の温度は、いずれの重合工程の重合においても、30〜200℃が好ましく、50〜150℃がより好ましい。 The temperature at which the radical polymerization is carried out is preferably 30 to 200 ° C, more preferably 50 to 150 ° C, in any of the polymerization steps.
ラジカル重合には通常の重合開始剤を用いることができる。重合開始剤としては、例えば、ジメチル−2,2’−アゾビス(2−メチルプロピオネート)(V−601と略す)、2,2’−アゾビスイソブチロニトリル、2,2’−アゾビス(2−メチルブチロニトリル)、2,2’−アゾビス(2,4−ジメチルバレロニトリル)、2,2’−アゾビスイソ酪酸ジメチルなどのアゾ系開始剤;過酸化ベンゾイルなどの過酸化物系重合開始剤;などを挙げることができ、これらの1種のみ用いてもよいし、2種以上を併用してもよい。重合開始剤の例としては、好ましくはジメチル−2,2’−アゾビス(2−メチルプロピオネート)(V−601)が挙げられる。ラジカル重合において用いる重合開始剤の全使用量は、質量比で、多価メルカプタンの1/3以下が好ましく、1/5以下がより好ましい。重合開始剤を上記比率よりも多量に使用すると、メルカプト基の硫黄残基から伸びた鎖状ポリマー部分以外に、重合開始剤から伸びたポリマーも多量に生成してしまい、星型アクリル系ブロックポリマーの生成効率が低下し易く、また、得られた星型アクリル系ブロックポリマーの物性も低下し易いからである。重合開始剤を反応系に添加する際には、1度に投入してもよいし、分割して投入してもよい。分割投入の場合は、それぞれを一括投入してもよいし、逐次投入してもよい。
A usual polymerization initiator can be used for radical polymerization. Examples of the polymerization initiator include dimethyl-2,2′-azobis (2-methylpropionate) (abbreviated as V-601), 2,2′-azobisisobutyronitrile, 2,2′-azobis Azo initiators such as (2-methylbutyronitrile), 2,2′-azobis (2,4-dimethylvaleronitrile) and
ラジカル重合には通常の溶剤を用いることができる。溶剤としては、例えば、酢酸エチル、酢酸プロピル、酢酸ブチルなどのエステル系溶剤;メチルエチルケトン、シクロヘキサノンなどのケトン系溶剤;ベンゼン、トルエンなどの芳香族系溶剤;メチルセロソルブ、エチルセロソルブなどのセロソルブ系溶剤;などが挙げられ、これらの1種のみ用いてもよいし、2種以上を併用してもよい。 A usual solvent can be used for radical polymerization. Examples of the solvent include ester solvents such as ethyl acetate, propyl acetate and butyl acetate; ketone solvents such as methyl ethyl ketone and cyclohexanone; aromatic solvents such as benzene and toluene; cellosolve solvents such as methyl cellosolve and ethyl cellosolve; These may be used alone or in combination of two or more.
星型アクリル系ブロックポリマーを製造するための特に好適な方法においては、第2重合工程(3段階以上の重合工程を含む場合には最後の重合工程)で使用する重合性モノマーの全ての反応系への供給が完了した後に、ブースターをさらに後添加することが好ましい。ブースターとしては、前述の重合開始剤が挙げられ、これらの1種のみ用いてもよいし、2種以上を併用してもよい。ブースターの全使用量は、特に限定されないが、重合性モノマーの全使用量に対して、好ましくは0.1〜5質量%、より好ましくは0.2〜2質量%、さらに好ましくは0.3〜1質量%である。ブースターの全使用量が0.1質量%未満であると、ブースターの効果が発現できず、5質量%を超えると、低分子量物が著しく生成して物性低下を招き、不経済である。ブースターの添加方法としては、特に限定されないが、例えば、連続的に滴下する連続滴下法や、一定時間毎に添加する分割滴下法が挙げられる。ブースターを添加する際の温度としては、特に限定されないが、30〜200℃が好ましく、50〜150℃がより好ましい。ブースターの添加時間としては、特に限定されないが、1〜10時間が好ましく、2〜8時間がより好ましい。 In a particularly preferable method for producing a star-shaped acrylic block polymer, all reaction systems of the polymerizable monomer used in the second polymerization step (the last polymerization step when three or more polymerization steps are included) are used. It is preferable to further add a booster after the feed to the feed is completed. Examples of the booster include the above-mentioned polymerization initiators, and one type thereof may be used alone, or two or more types may be used in combination. Although the total amount of the booster is not particularly limited, it is preferably 0.1 to 5% by mass, more preferably 0.2 to 2% by mass, and still more preferably 0.3% by mass, based on the total amount of the polymerizable monomer. 11% by mass. If the total amount of the booster is less than 0.1% by mass, the effect of the booster cannot be exhibited, and if it exceeds 5% by mass, a low-molecular-weight substance is remarkably generated to cause deterioration in physical properties, which is uneconomical. The method of adding the booster is not particularly limited, and includes, for example, a continuous dropping method of continuously dropping, and a split dropping method of adding at regular intervals. Although the temperature at the time of adding a booster is not specifically limited, 30-200 degreeC is preferable and 50-150 degreeC is more preferable. The time for adding the booster is not particularly limited, but is preferably 1 to 10 hours, more preferably 2 to 8 hours.
ブースターの添加が完了した後は、好ましくは30〜200℃、より好ましくは50〜150℃で、反応系をさらに熟成させてもよい。具体的には、用いる溶剤の還流条件下(前記温度範囲内)で行うことが好ましい。熟成時間は、特に限定されないが、好ましくは1時間以上、より好ましくは2時間以上、さらに好ましくは3時間以上である。熟成時間の上限は特に限定されないが、通常は、20時間以内とすることが好ましい。 After the addition of the booster is completed, the reaction system may be further aged at preferably 30 to 200 ° C, more preferably 50 to 150 ° C. Specifically, it is preferable to carry out the reaction under the reflux condition of the solvent used (within the above temperature range). The aging time is not particularly limited, but is preferably 1 hour or more, more preferably 2 hours or more, and still more preferably 3 hours or more. The upper limit of the aging time is not particularly limited, but is usually preferably within 20 hours.
星型アクリル系ブロックポリマーを製造するための特に好適な方法においては、第2重合工程における重合開始時から前記熟成終了までの総時間が、好ましくは8〜20時間、より好ましくは12〜20時間、さらに好ましくは15〜20時間である。第2重合工程における重合開始時から前記熟成終了までの総時間が8時間よりも短いと、得られる星型アクリル系ブロックポリマーにおいて本発明の効果が十分に発揮できず、特に、炭素数7〜17の(メタ)アクリル酸アルキルエステルの残存量が増えてしまうので好ましくない。第2重合工程における重合開始時から前記熟成終了までの総時間が20時間よりも長いと、生産性が著しく低下するとともにエネルギーコストが増大するという問題が生じるとともに、得られる星型アクリル系ブロックポリマーの性能も低下するおそれがあるので好ましくない。 In a particularly preferred method for producing a star-shaped acrylic block polymer, the total time from the start of polymerization in the second polymerization step to the end of the ripening is preferably 8 to 20 hours, more preferably 12 to 20 hours. And more preferably for 15 to 20 hours. If the total time from the start of the polymerization in the second polymerization step to the end of the aging is shorter than 8 hours, the effect of the present invention cannot be sufficiently exerted in the obtained star-shaped acrylic block polymer, and in particular, the number of carbon atoms is 7 to 7. It is not preferable because the remaining amount of the alkyl (meth) acrylate 17 increases. If the total time from the start of the polymerization in the second polymerization step to the end of the aging is longer than 20 hours, there is a problem that productivity is remarkably reduced and energy cost is increased, and the obtained star-shaped acrylic block polymer is obtained. Is also not preferred because the performance of the device may also decrease.
星型アクリル系ブロックポリマーを製造するために好適な方法としては、以上述べた以外にも、星型アクリル系ブロックポリマーの従来の製造方法において用いられる一般的な方法が適宜用いられてもよい。 As a suitable method for producing the star-shaped acrylic block polymer, a general method used in a conventional method for producing a star-shaped acrylic block polymer may be appropriately used, in addition to the above.
星型アクリル系ブロックポリマーは、ポリマー溶液の状態で得られることが一般的である。星型アクリル系ブロックポリマーが溶液の状態で得られる場合、溶液中の不揮発分の含有割合は総計で、好ましくは40〜70質量%、より好ましくは45〜65質量%、さらに好ましくは45〜60質量%である。溶液中の不揮発分の含有割合が総計で40質量%未満であると、溶液粘度が低くなって塗工しにくくなり、また、揮発させる溶剤量が多くなるため、乾燥に多くのエネルギーを必要として不経済である。70質量%を超えると、溶液の粘度が著しく増加するためにハンドリングが悪くなる。 The star-shaped acrylic block polymer is generally obtained in a state of a polymer solution. When the star-shaped acrylic block polymer is obtained in the form of a solution, the content of nonvolatile components in the solution is preferably 40 to 70% by mass, more preferably 45 to 65% by mass, and still more preferably 45 to 60% by mass. % By mass. If the total content of the non-volatile components in the solution is less than 40% by mass, the solution viscosity becomes low and coating becomes difficult, and the amount of the solvent to be volatilized increases, so that much energy is required for drying. It is uneconomical. If it exceeds 70% by mass, the viscosity of the solution is remarkably increased, so that handling becomes poor.
本発明において、上記粘着剤は、単独で使用されてもあるいは2種以上の混合物の形態で使用されてもよい。これらのうち、アクリル系ポリマーおよび星型アクリル系ブロックポリマーが好ましく、特に星型アクリル系ブロックポリマーが粘着力と凝集力との優れたバランスにより好ましい。粘着剤は、粘着剤組成物中に総計で50〜99.9質量%配合され、好ましくは50〜99質量%、より好ましくは50〜95質量%の量で配合される。 In the present invention, the above-mentioned pressure-sensitive adhesive may be used alone or in the form of a mixture of two or more kinds. Among these, an acrylic polymer and a star-shaped acrylic block polymer are preferred, and a star-shaped acrylic block polymer is particularly preferred because of its excellent balance between adhesion and cohesion. The pressure-sensitive adhesive is incorporated in the adhesive composition in a total amount of 50 to 99.9% by mass, preferably 50 to 99% by mass, more preferably 50 to 95% by mass.
本発明の医療用貼付剤の粘着剤組成物には、さらに、薬物の経皮吸収性を向上させるため経皮吸収促進剤等を添加することができる。経皮吸収促進剤としては、限定されるものではないが、ミリスチン酸イソプロピル、アジピン酸ジイソプロピル、ミリスチン酸ミリスチル、ミリスチン酸オクチルドデシル、パルミチン酸イソプロピル、ステアリン酸ブチル、ラウリン酸ヘキシル、オレイン酸デシル等の脂肪酸エステル、カプリル酸、カプリン酸、イソステアリン酸、オレイン酸、ミリスチン酸等の高級脂肪酸、ジイソプロパノールアミン、トリエタノールアミン等のアミン類、プロピレングリコールモノラウレート、プロピレングリコール脂肪酸エステル、グリセリン脂肪酸エステル、ソルビタン脂肪酸エステル、ショ糖脂肪酸エステル等の多価アルコール脂肪酸エステル、ポリエチレングリコール、プロピレングリコール、ブチレングリコール、グリコール等の多価アルコール、モノオレイン酸ソルビタン、ラウロマクロゴール、ラウリルアルコール等の界面活性剤等、クロタミトン、N−メチルピロリドン等が挙げられ、これらの1種のみ用いてもよいし、2種以上を併用してもよい。 To the pressure-sensitive adhesive composition of the medical patch of the present invention, a transdermal absorption enhancer or the like can be further added in order to improve the transdermal absorbability of the drug. Transdermal absorption enhancers include, but are not limited to, isopropyl myristate, diisopropyl adipate, myristyl myristate, octyl dodecyl myristate, isopropyl palmitate, butyl stearate, hexyl laurate, decyl oleate, and the like. Fatty acid esters, higher fatty acids such as caprylic acid, capric acid, isostearic acid, oleic acid, and myristic acid, amines such as diisopropanolamine and triethanolamine, propylene glycol monolaurate, propylene glycol fatty acid esters, glycerin fatty acid esters, and sorbitan Polyhydric alcohol fatty acid esters such as fatty acid esters and sucrose fatty acid esters, and polyhydric alcohols such as polyethylene glycol, propylene glycol, butylene glycol, and glycol , Sorbitan monooleate, lauromacrogol, lauryl alcohol, etc., crotamiton, N-methylpyrrolidone, etc., and these may be used alone or in combination of two or more. Is also good.
さらに本発明の医療用貼付剤の粘着剤組成物には、粘着基剤の接着性・安定性の調整のために、必要に応じて、通常の貼付剤に用いられる添加成分が、適宜選択され、使用できる。例えば、ポリビニルピロリドン、ポリビニルアルコール等の水溶性高分子、エチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース等のセルロース誘導体、無水ケイ酸、軽質無水ケイ酸等のケイ素化合物、酸化亜鉛、酸化アルミニウム、酸化マグネシウム、酸化鉄、二酸化チタン、シリカ類等の無機充填剤、およびジブチルヒドロキシトルエン等の酸化防止剤などを適宜適量含有させることができる。また、本発明の医療用貼付剤の粘着剤組成物には、必要に応じて架橋剤、粘着付与剤、軟化剤、可塑剤等が配合されてもよい。さらに本発明の医療用貼付剤の粘着剤組成物には、必要に応じて防腐剤、清涼剤、殺菌剤、着香剤、着色剤等を配合することができる。これら必要に応じて使用できる成分は、特に制限されず、公知のものを適宜適量使用することができる。 Further, in the pressure-sensitive adhesive composition of the medical patch of the present invention, for the purpose of adjusting the adhesiveness and stability of the pressure-sensitive adhesive base, if necessary, additional components used in normal patches are appropriately selected. , Available. For example, polyvinylpyrrolidone, water-soluble polymers such as polyvinyl alcohol, ethyl cellulose, hydroxypropyl cellulose, cellulose derivatives such as hydroxypropylmethyl cellulose, silicic anhydride, silicon compounds such as light silicic anhydride, zinc oxide, aluminum oxide, magnesium oxide, An appropriate amount of an inorganic filler such as iron oxide, titanium dioxide and silica, and an antioxidant such as dibutylhydroxytoluene can be appropriately contained. Further, the pressure-sensitive adhesive composition of the medical patch of the present invention may contain a crosslinking agent, a tackifier, a softener, a plasticizer, and the like, if necessary. Further, the pressure-sensitive adhesive composition of the medical patch of the present invention may contain, if necessary, a preservative, a refreshing agent, a bactericide, a flavoring agent, a coloring agent and the like. The components that can be used as necessary are not particularly limited, and known components can be used in appropriate amounts.
本発明の医療用貼付剤に用いられる塩基性薬物の塩としては、塩基性薬物のクエン酸塩、コハク酸塩、フマル酸塩、マレイン酸塩、酒石酸塩等のカルボン酸塩や、塩酸塩、硫酸塩、リン酸塩等が挙げられ、例えば麻薬系鎮痛剤(クエン酸フェンタニル、硫酸モルヒネ、塩酸オキシコドン、塩酸ブプレノルフィン)、泌尿器用薬(塩酸オキシブチニン、塩酸タムスロシン、酒石酸トルテロジン等)、抗パーキンソン薬(メシル酸ラサギリン、メシル酸ペルゴリド、塩酸アマンタジン、塩酸トリヘキシフェニジル、塩酸ロピニロール等)、局所麻酔剤(塩酸リドカイン、塩酸プロカイン等)、抗認知症薬(塩酸ドネペジル、塩酸メマンチン等)、精神神経用剤(クエン酸タンドスピロン、塩酸メチルフェニデート、塩酸ルラシドン、塩酸クロルプロマジン、塩酸イミプラミン、マレイン酸アセナピン等)、気管支拡張剤(硫酸サルブタモール、塩酸クレンブテロール、塩酸ツロブテロール、塩酸プロカテロール等)、消炎鎮痛剤(酒石酸ブトルファノール、クエン酸ペリソキサール等)、血圧降下薬(マレイン酸エナラプリル、塩酸プロプラノロール、塩酸ビソプロロール、塩酸クロニジン)、冠血管拡張薬(塩酸ジルチアゼム、塩酸ベラパミル、硝酸イソソルビド等)、抗アレルギー薬(フマル酸ケトチフェン、マレイン酸クロルフェニラミン、塩酸アゼラスチン、塩酸ジフェンヒドラミン等)、セロトニン受容体拮抗薬(塩酸グラニセトロン、塩酸ラモセトロン、塩酸パロノセトロン、塩酸オンダンセトロン等)が挙げられる。これらの薬効成分は、単独で用いても、2種類以上組み合わせてもよく、粘着剤組成物中に総計で0.1〜50質量%配合され、好ましくは1〜50質量%、より好ましくは5〜50質量%の量で配合される。 As the salt of the basic drug used in the medical patch of the present invention, citrate of the basic drug, succinate, fumarate, maleate, carboxylate such as tartrate, hydrochloride, Examples thereof include sulfates and phosphates, and examples thereof include narcotic analgesics (fentanyl citrate, morphine sulfate, oxycodone hydrochloride, buprenorphine hydrochloride), urinary drugs (oxybutynin hydrochloride, tamsulosin hydrochloride, tolterodine tartrate, etc.), antiparkinson drugs ( Rasagiline mesylate, pergolide mesylate, amantadine hydrochloride, trihexyphenidyl hydrochloride, ropinirole hydrochloride, etc., local anesthetics (lidocaine hydrochloride, procaine hydrochloride, etc.), nootropics (donepezil hydrochloride, memantine hydrochloride, etc.), for psychiatric nerves Agents (tandospirone citrate, methylphenidate hydrochloride, lurasidone hydrochloride, chlorp hydrochloride Mazine, imipramine hydrochloride, asenapine maleate, etc.), bronchodilators (salbutamol sulfate, clenbuterol hydrochloride, tulobuterol hydrochloride, procaterol hydrochloride, etc.), anti-inflammatory analgesics (butorphanol tartrate, perisoxal citrate, etc.), antihypertensive drugs (enalapril maleate, Propranolol hydrochloride, bisoprolol hydrochloride, clonidine hydrochloride, coronary vasodilators (diltiazem hydrochloride, verapamil hydrochloride, isosorbide dinitrate, etc.), antiallergic drugs (ketotifen fumarate, chlorpheniramine maleate, azelastine hydrochloride, diphenhydramine hydrochloride, etc.), serotonin receptor Body antagonists (granisetron hydrochloride, ramosetron hydrochloride, palonosetron hydrochloride, ondansetron hydrochloride, etc.). These medicinal ingredients may be used alone or in combination of two or more, and are incorporated in the adhesive composition in a total of 0.1 to 50% by mass, preferably 1 to 50% by mass, more preferably 5 to 50% by mass. It is blended in an amount of 5050% by mass.
本発明の医療用貼付剤における支持体は、特に限定されるものではなく、貼付剤用として通常用いられる伸縮性または非伸縮性のものが用いられる。具体的には、例えばポリエチレンテレフタレート、ポリエチレン、ポリプロピレン、ポリブタジエン、エチレン酢酸ビニル共重合体、ポリ塩化ビニル、ポリエステル、ナイロン、ポリウレタン等の合成樹脂で形成されたフィルムもしくはシートまたはこれらの積層体、多孔質膜、発泡体、織布、不織布、あるいは紙材を用いることができる。 The support in the medical patch of the present invention is not particularly limited, and a stretchable or non-stretchable one usually used for a patch is used. Specifically, for example, a film or sheet formed of a synthetic resin such as polyethylene terephthalate, polyethylene, polypropylene, polybutadiene, ethylene vinyl acetate copolymer, polyvinyl chloride, polyester, nylon, polyurethane, or a laminate of these, A film, a foam, a woven fabric, a nonwoven fabric, or a paper material can be used.
本発明の医療用貼付剤は、前記支持体上に積層された粘着剤層の上に剥離ライナーを付し、使用に際して、剥離ライナーを剥がして、粘着剤層の面を所望の皮膚に貼り付ける。 The medical patch of the present invention is such that a release liner is provided on the pressure-sensitive adhesive layer laminated on the support, and in use, the release liner is peeled off and the surface of the pressure-sensitive adhesive layer is attached to a desired skin. .
本発明の貼付剤に使用される剥離ライナーは、貼付剤用として通常用いられているものが用いられ、例えば、ポリエチレンテレフタレート、ポリプロピレン、紙等を用いることができ、特にポリエチレンテレフタレートが好ましい。剥離ライナーは剥離力を至適にするため、必要に応じてシリコン処理をしてもよい。 As the release liner used for the patch of the present invention, those commonly used for patches are used. For example, polyethylene terephthalate, polypropylene, paper and the like can be used, and polyethylene terephthalate is particularly preferable. The release liner may be siliconized as needed to optimize the release force.
また、本発明の医療用貼付剤には、保存中における主薬の安定性の向上のために、脱酸素剤を共存させてもよい。脱酸素剤としては鉄を原料とするものや、非鉄金属を原料とするものが好ましく用いられる。脱酸素剤の共存方法としては、包装容器に脱酸素剤を直接封入する方法、あるいは包装容器に脱酸素フィルムを積層した形態のものを使用する方法等が挙げられる。 Further, the medical patch of the present invention may be coexisted with an oxygen scavenger in order to improve the stability of the main drug during storage. As the oxygen scavenger, those using iron as a raw material and those using nonferrous metal as a raw material are preferably used. Examples of the coexisting method of the oxygen scavenger include a method of directly enclosing the oxygen scavenger in the packaging container, and a method of using a package in which the oxygen scavenging film is laminated on the packaging container.
本発明の医療用貼付剤は、例えば以下の方法によって製造することができる。塩基性薬物の塩を適当な溶媒に分散させ、薬液を調製する。別に、弱塩基モノマーを共重合させた星型アクリル系ブロックポリマー、およびその他の各成分を適当な溶媒に混合溶解または分散させ、粘着基剤を得る。溶媒としては、トルエン、酢酸エチル、エタノール、メタノール等が使用でき、成分に応じて適宜選択し、1種または2種以上を混合して使用できる。次に、粘着基剤に薬液を添加し、均一になるまで撹拌混合することによって得られた粘着剤溶液を、剥離ライナーまたは支持体上に伸展して溶媒を乾燥除去後、支持体または剥離ライナーと貼り合わせて本発明の医療用貼付剤を得ることができる。なお、粘着剤層の厚みは30〜200μm、より好ましくは30〜100μmである。30μm未満であると、薬物放出の持続性が乏しくなり、200μmを超えると、粘着剤層中の薬物含量が増え、残存薬物量の増加や製造コストの増加を引き起こす。 The medical patch of the present invention can be produced, for example, by the following method. A basic drug salt is dispersed in an appropriate solvent to prepare a drug solution. Separately, a star-shaped acrylic block polymer obtained by copolymerizing a weak base monomer and other components are mixed and dissolved or dispersed in an appropriate solvent to obtain an adhesive base. As the solvent, toluene, ethyl acetate, ethanol, methanol, and the like can be used, and they can be appropriately selected according to the components, and can be used alone or in combination of two or more. Next, a chemical solution is added to the pressure-sensitive adhesive base, and the pressure-sensitive adhesive solution obtained by stirring and mixing until uniform is spread on a release liner or a support, and after removing the solvent by drying, the support or the release liner is removed. And the medical patch of the present invention can be obtained. In addition, the thickness of an adhesive layer is 30-200 micrometers, More preferably, it is 30-100 micrometers. If it is less than 30 μm, the sustainability of drug release will be poor, and if it exceeds 200 μm, the drug content in the pressure-sensitive adhesive layer will increase, causing an increase in the amount of residual drug and an increase in manufacturing cost.
以下、製造例あるいは実施例により本発明をさらに詳細に説明するが、本発明はこれらに限定されるものではない。なお、下記実施例および比較例において、特記しない限り、「部」および「%」は、それぞれ、「質量部」および「質量%」を表す。なお、数平均分子量(Mn)、重量平均分子量(Mw)は、ゲルパーミエーションクロマトグラフィー(GPC)によりポリスチレン換算値で求めた。 Hereinafter, the present invention will be described in more detail with reference to Production Examples or Examples, but the present invention is not limited thereto. In the following Examples and Comparative Examples, “parts” and “%” represent “parts by mass” and “% by mass”, respectively, unless otherwise specified. The number average molecular weight (Mn) and weight average molecular weight (Mw) were determined in terms of polystyrene by gel permeation chromatography (GPC).
〔アクリル粘着剤の調製〕
〔製造例1〕
1.1段階目の重合:中間ポリマー溶液の合成
温度計、撹拌機、不活性ガス導入管、還流冷却器および滴下ロートを備えた4つ口フラスコにメタクリル酸メチル24部、ジペンタエリスリトール−β−メルカプトプロピオネート(以下DPMPと略記)1.2部、および溶剤として酢酸エチル24.82部を仕込んだ。窒素気流下に撹拌し、83±2℃に保って重合開始剤としてジメチル−2,2’−アゾビス(2−メチルプロピオネート)(商品名:V−601、和光純薬工業社製、以下V−601と略記)0.048部および溶解溶剤として酢酸エチル0.432部を加えて重合を開始させた。反応開始から30分後にメタクリル酸メチル56部および酢酸エチル15.25部を120分かけて、またV−601溶液(V−601:0.084部、DPMP2.8部および酢酸エチル2.8部の混合物)を90分かけて滴下し、内温を還流下で制御しながら反応を行った。メタクリル酸メチル滴下終了後に酢酸エチル2部を添加し、さらに130分反応を行った。その後、重合禁止剤溶液(ハイドロキノンモノメチルエーテル0.04部および酢酸エチル0.36部からなる混合物)と希釈用酢酸エチル38.431部を加えて冷却し、粘着剤用中間ポリマー溶液(A1)を得た。得られた中間ポリマー溶液(A1)は、不揮発分34.5%、粘度90mPa・sであった。(Preparation of acrylic adhesive)
[Production Example 1]
First Stage Polymerization: Synthesis of Intermediate Polymer Solution In a four-necked flask equipped with a thermometer, a stirrer, an inert gas inlet tube, a reflux condenser, and a dropping funnel, 24 parts of methyl methacrylate, dipentaerythritol-β 1.2 parts of mercaptopropionate (hereinafter abbreviated as DPMP) and 24.82 parts of ethyl acetate as a solvent were charged. The mixture was stirred under a nitrogen stream and kept at 83 ± 2 ° C., and dimethyl-2,2′-azobis (2-methylpropionate) (trade name: V-601, manufactured by Wako Pure Chemical Industries, Ltd.) was used as a polymerization initiator. The polymerization was started by adding 0.048 parts of V-601) and 0.432 parts of ethyl acetate as a dissolving solvent. Thirty minutes after the start of the reaction, 56 parts of methyl methacrylate and 15.25 parts of ethyl acetate were added over 120 minutes, and a V-601 solution (V-601: 0.084 part, DPMP 2.8 parts and ethyl acetate 2.8 parts) was added. Was added dropwise over 90 minutes, and the reaction was carried out while controlling the internal temperature under reflux. After the completion of the dropwise addition of methyl methacrylate, 2 parts of ethyl acetate was added, and the reaction was further performed for 130 minutes. Thereafter, a polymerization inhibitor solution (a mixture of 0.04 part of hydroquinone monomethyl ether and 0.36 part of ethyl acetate) and 38.431 parts of ethyl acetate for dilution are added, and the mixture is cooled. The intermediate polymer solution for adhesive (A1) is then added. Obtained. The obtained intermediate polymer solution (A1) had a nonvolatile content of 34.5% and a viscosity of 90 mPa · s.
2.2段階目の反応:粘着剤用ポリマーの合成
温度計、撹拌機、不活性ガス導入管、還流冷却器および滴下ロートを備えた4つ口フラスコに上記の反応で得られた中間ポリマー溶液(A1)15.22部、アクリル酸ブチル8.49部、アクリル酸2−エチルヘキシル6.85部、酢酸ビニル1.10部、メタクリル酸ジメチルアミノエチル10.96部、および溶剤として酢酸エチル11部を仕込んだ。窒素気流下に撹拌し、83±2℃に保って重合開始剤としてV−601溶液(V−601の0.02部と酢酸エチル1部の混合物)を加えて重合を開始させた。反応開始から10分後に中間ポリマー溶液(A1)15.22部、アクリル酸ブチル8.49部、アクリル酸2−エチルヘキシル6.85部、酢酸ビニル1.10部、メタクリル酸ジメチルアミノエチル10.96部、および溶剤として酢酸エチル10部からなるモノマー混合物と、V−601溶液(V−601:0.02部および酢酸エチル4部の混合物)とを80分かけて滴下し、還流下で制御しながら反応を行った。滴下終了後に酢酸エチル1部を添加し、さらに3時間30分反応を続けた。その後、ブースターとしてV−601溶液(V−601:0.08部および酢酸エチル4部の混合物)を1時間かけて滴下し、さらに還流下で10時間反応を続けた。その後、希釈溶剤として酢酸エチルを20.3部添加し、冷却し粘着剤用ポリマー溶液(B1)を得た。得られたポリマー溶液(B1)は、不揮発分47.6%、粘度500mPa・sであった。生成した重合体の数平均分子量(Mn)は30,000、重量平均分子量(Mw)は77,000であった。2.2 Reaction of the Second Step: Synthesis of Polymer for Adhesive The intermediate polymer solution obtained in the above reaction in a four-necked flask equipped with a thermometer, a stirrer, an inert gas inlet tube, a reflux condenser, and a dropping funnel. (A1) 15.22 parts, butyl acrylate 8.49 parts, 2-ethylhexyl acrylate 6.85 parts, vinyl acetate 1.10 parts, dimethylaminoethyl methacrylate 10.96 parts, and 11 parts of ethyl acetate as a solvent Was charged. The mixture was stirred under a nitrogen stream, and kept at 83 ± 2 ° C., a polymerization initiator V-601 solution (a mixture of 0.02 part of V-601 and 1 part of ethyl acetate) was added to initiate polymerization. Ten minutes after the start of the reaction, 15.22 parts of the intermediate polymer solution (A1), 8.49 parts of butyl acrylate, 6.85 parts of 2-ethylhexyl acrylate, 1.10 parts of vinyl acetate, and 10.96 parts of dimethylaminoethyl methacrylate And a monomer mixture consisting of 10 parts of ethyl acetate as a solvent and a V-601 solution (a mixture of 0.02 parts of V-601 and 4 parts of ethyl acetate) were added dropwise over 80 minutes and controlled under reflux. The reaction was carried out. After completion of the dropwise addition, 1 part of ethyl acetate was added, and the reaction was further continued for 3 hours and 30 minutes. Thereafter, a V-601 solution (V-601: a mixture of 0.08 parts and 4 parts of ethyl acetate) was added dropwise as a booster over 1 hour, and the reaction was further continued under reflux for 10 hours. Thereafter, 20.3 parts of ethyl acetate was added as a diluting solvent, and the mixture was cooled to obtain a polymer solution for an adhesive (B1). The obtained polymer solution (B1) had a nonvolatile content of 47.6% and a viscosity of 500 mPa · s. The number average molecular weight (Mn) of the produced polymer was 30,000, and the weight average molecular weight (Mw) was 77,000.
また、上記製造例で使用される特性は、以下の方法によって測定・評価した。
〔粘着剤のスペック測定方法〕
(1)粘度
B型粘度計を用いて、25℃で測定した。回転数は毎分12回転とした。
(2)不揮発分
熱風循環乾燥機中で150℃×15分間乾燥させて、質量変化より算出した。The properties used in the above Production Examples were measured and evaluated by the following methods.
[Adhesive specification measurement method]
(1) Viscosity It was measured at 25 ° C. using a B-type viscometer. The number of revolutions was 12 revolutions per minute.
(2) Non-volatile content It was dried in a hot-air circulating drier at 150 ° C. for 15 minutes and calculated from the change in mass.
〔貼付剤の調製〕
〔実施例1〕
メシル酸ラサギリンを酢酸エチルに分散させ、薬液を調製した。次に、製造例1のアクリル粘着剤に薬液を添加し、均一になるまで撹拌混合することによって得られた粘着剤組成物を、剥離ライナー上に伸展して溶媒を乾燥除去させ、厚さ30μmの粘着剤層を形成後、支持体を貼り合せることにより医療用貼付剤を得た。なお各成分の配合比は表1−1に示す通りである。(Preparation of patch)
[Example 1]
Rasagiline mesylate was dispersed in ethyl acetate to prepare a drug solution. Next, a chemical solution was added to the acrylic pressure-sensitive adhesive of Production Example 1, and the pressure-sensitive adhesive composition obtained by stirring and mixing until uniform was spread on a release liner, the solvent was removed by drying, and the thickness was 30 μm. After the pressure-sensitive adhesive layer was formed, the support was laminated to obtain a medical patch. The mixing ratio of each component is as shown in Table 1-1.
〔実施例2〕
メシル酸ラサギリンをマレイン酸アセナピンに変更した以外は、下記表1−1に示す処方構成で、実施例1の製法に従い、実施例2の医療用貼付剤を製造した。[Example 2]
The medical patch of Example 2 was manufactured according to the manufacturing method of Example 1 with the formulation shown in Table 1-1 below, except that rasagiline mesylate was changed to asenapine maleate.
〔比較例1〜7〕
メシル酸ラサギリンを酢酸エチルに分散させ、薬液を調製した。次に、アクリル系粘着剤DURO−TAK 87−4098(ヘンケル社製)またはDURO−TAK 87−9301(ヘンケル社製)に薬液を添加し、さらに、ジエタノールアミン、酢酸ナトリウムまたはEUDRAGIT E−100(アミノアルキルメタクリレートポリマー)から選択される1種の塩基性添加物を添加し、均一になるまで撹拌混合することによって得られた粘着剤組成物を、剥離ライナー上に進展して溶媒を乾燥除去させ、厚さ30μmの粘着剤層を形成後、支持体を貼り合せることにより医療用貼付剤を得た。なお各成分の配合比は表1−2、および表1−3に示す通りである。[Comparative Examples 1 to 7]
Rasagiline mesylate was dispersed in ethyl acetate to prepare a drug solution. Next, a chemical solution was added to the acrylic adhesive DURO-TAK 87-4098 (manufactured by Henkel) or DURO-TAK 87-9301 (manufactured by Henkel), and further, diethanolamine, sodium acetate or EUDRAGIT E-100 (aminoalkyl) One type of basic additive selected from methacrylate polymer) is added, and the pressure-sensitive adhesive composition obtained by stirring and mixing until uniform is developed on a release liner, and the solvent is removed by drying. After forming a 30 μm-thick pressure-sensitive adhesive layer, the support was laminated to obtain a medical patch. The mixing ratio of each component is as shown in Tables 1-2 and 1-3.
〔比較例8〜10〕
メシル酸ラサギリンをマレイン酸アセナピンに変更した以外は、下記表1−4に示す処方構成で、上記比較例1〜7の製法に従い、比較例8〜10の医療用貼付剤を製造した。[Comparative Examples 8 to 10]
Except that rasagiline mesylate was changed to asenapine maleate, the medical patches of Comparative Examples 8 to 10 were produced in accordance with the production methods of Comparative Examples 1 to 7 above with the formulation shown in Tables 1-4 below.
実施例1〜2及び比較例1〜10に記載の医療用貼付剤の組成を下記の〔表1−1〕〜〔表1〜4〕に示す。
〔試験例1〕:プローブタック試験
本発明の医療用貼付剤の粘着力(タック力)を評価するため、実施例1〜2および比較例1〜10について、プローブタック試験を行った。直径5mmの球状のSUS製プローブを、毎分10mmの速度で粘着面に接近させ、10秒間接触後、毎分300mmの速度で引き剥がした際の、荷重を測定した。実施例1及び比較例1〜6までの結果を表2−1に、実施例2及び比較例8〜10までの結果を表2−2に示す。結果は、薬物および添加物を含有しない粘着剤単体のタック力を100とした場合のタック力の比(%)で示し、薬物および添加物を加えた場合の粘着剤組成物に与える影響を評価した。[Test Example 1]: Probe tack test In order to evaluate the adhesive strength (tack strength) of the medical patch of the present invention, a probe tack test was performed on Examples 1 and 2 and Comparative Examples 1 to 10. A load was measured when a spherical SUS probe having a diameter of 5 mm was brought close to the adhesive surface at a speed of 10 mm per minute, contacted for 10 seconds, and peeled off at a speed of 300 mm per minute. Table 2-1 shows the results of Example 1 and Comparative Examples 1 to 6, and Table 2-2 shows the results of Example 2 and Comparative Examples 8 to 10. The results are shown as a ratio (%) of the tacking force when the tacking force of the pressure-sensitive adhesive alone containing no drug or additive is set to 100, and the effect of the drug and the additive on the pressure-sensitive adhesive composition is evaluated. did.
表2に示す試験結果より、本発明の貼付剤は、各比較例の貼付剤と比較し、高いタック力を示した。これはすなわち、本発明の貼付剤は塩基性薬物の塩の遊離塩基への変換に必要な添加剤の配合が不要のため、それらの配合によるタック力の低下が起こらず、優れた粘着性を示す製剤であることが示されている。 From the test results shown in Table 2, the patch of the present invention exhibited higher tackiness than the patches of Comparative Examples. That is, since the patch of the present invention does not require the addition of additives required for converting a salt of a basic drug to a free base, the tack force does not decrease due to the addition of the additives, and excellent adhesiveness is obtained. It is shown to be the indicated formulation.
〔試験例2〕:剥離試験
本発明の医療用貼付剤の粘着力(剥離力)を評価するため、実施例1および比較例1〜6について、剥離試験を行った。SUS300番研磨の試験板に1cm×5cmに調製した各貼付剤を貼り付け、毎分300mmの速度で引き剥がす際の荷重を測定した。結果を表3に示す。結果は、薬物および添加物を含有しない粘着剤単体の剥離力を100とした場合の剥離力の比(%)で示し、薬物および添加物を加えた場合の粘着剤組成物に与える影響を評価した。[Test Example 2]: Peeling test In order to evaluate the adhesive strength (peeling force) of the medical patch of the present invention, a peeling test was performed on Example 1 and Comparative Examples 1 to 6. Each patch prepared in a size of 1 cm × 5 cm was adhered to a SUS300 polishing test plate, and the load at the time of peeling at a speed of 300 mm per minute was measured. Table 3 shows the results. The results are shown as a ratio (%) of the peeling force when the peeling force of the pressure-sensitive adhesive alone containing no drug and the additive is set to 100, and the effect of the drug and the additive on the pressure-sensitive adhesive composition is evaluated. did.
上記試験結果より、本発明の貼付剤は、各比較例の貼付剤と比較し、高い剥離力を示した。これはすなわち、本発明の貼付剤は塩基性薬物の塩の遊離塩基への変換に必要な添加剤の配合が不要のため、それらの配合による剥離力の低下が起こらず、優れた粘着性を示す製剤であることが示されている。 From the above test results, the patch of the present invention showed a higher peeling force than the patches of Comparative Examples. That is, since the patch of the present invention does not require the addition of additives necessary for converting a salt of a basic drug into a free base, the peeling force does not decrease due to the addition of the additives, and excellent adhesiveness is obtained. It is shown to be the indicated formulation.
〔試験例3〕熱安定性(粘着力物性)
60℃で2週間保存した、実施例1および比較例1、4の製剤について、試験例1および試験例2と同様の方法でタック力および剥離力を評価した。結果を表4に示す。結果は、薬物および添加物を含有しない粘着剤単体のタック力あるいは剥離力を100とした場合のタック力あるいは剥離力の比(%)で示し、薬物および添加物を加えた場合の粘着剤組成物に与える影響を評価した。[Test Example 3] Thermal stability (adhesive properties)
For the preparations of Example 1 and Comparative Examples 1 and 4 stored at 60 ° C. for 2 weeks, the tack force and the peeling force were evaluated in the same manner as in Test Examples 1 and 2. Table 4 shows the results. The results are shown as a ratio (%) of the tacking force or the peeling force when the tacking force or the peeling force of the pressure-sensitive adhesive alone containing no drug and the additive is 100, and the pressure-sensitive adhesive composition when the drug and the additive are added. The effects on objects were evaluated.
表4に示す試験結果より、本発明の貼付剤は、各比較例の貼付剤と比較し、高いタック力および剥離力を示した。これはすなわち、本発明の貼付剤は塩基性薬物の塩の遊離塩基への変換に必要な添加剤の配合が不要のため、それらの配合によるタック力および剥離力の低下が起こらず、優れた粘着性を示す製剤であることが示されている。 From the test results shown in Table 4, the patch of the present invention exhibited higher tack and peeling strength than the patches of Comparative Examples. That is, since the patch of the present invention does not require the addition of additives necessary for converting a salt of a basic drug to a free base, the tack force and the peeling force due to those compounds do not decrease, and the patch is excellent. It is shown to be a sticky formulation.
また、本試験の結果において、各比較例の粘着力が試験例1あるいは試験例2を実施した場合と比較して、著しく低下しているのに比べ、実施例1の粘着力は、試験例1および試験例2の試験結果と同様、粘着剤単体とほとんど遜色ない粘着性を示す結果となっている。これは、高温保存状態という過酷な保存条件であっても、本発明の優れた効果が維持されることを示している。 In addition, in the results of this test, the adhesive strength of each comparative example was significantly reduced as compared with the case where test example 1 or test example 2 was performed. Similar to the test results of Test Example 1 and Test Example 2, the result shows that the adhesiveness is almost the same as that of the pressure-sensitive adhesive alone. This indicates that the excellent effects of the present invention can be maintained even under severe storage conditions such as a high-temperature storage state.
〔試験例4〕:in vitroヘアレスラット皮膚透過性試験
本発明の貼付剤におけるラサギリンの経皮吸収性を検討するため、各実施例1、比較例3および比較例7の貼付剤について、ヘアレスラットにおけるin vitro皮膚透過性試験を行った。但し、各製剤とも粘着剤層の厚みを100μmに調整した。ヘアレスラット(HWY系、7週齢)の腹部摘出皮膚をフランツ型拡散セルにセットし、円形(φ14mm)に裁断した各試験製剤を貼付した。レセプター側にはリン酸緩衝生理食塩水を満たし、ウォータージャケットには、37℃の温水を還流した。経時的にレセプター液をサンプリングし、皮膚を透過したラサギリン量を液体クロマトグラフ法により測定し、その結果より、試験開始8時間後、および16時間後の経皮吸収速度(Flux:μg/cm2/h)を算出した。その結果を、表5に示す。[Test Example 4]: In Vitro Hairless Rat Skin Permeability Test In order to examine the transdermal absorbability of rasagiline in the patch of the present invention, the patch of each Example 1, Comparative Example 3 and Comparative Example 7 was tested for hairless rats. An in vitro skin permeability test was performed in However, in each preparation, the thickness of the pressure-sensitive adhesive layer was adjusted to 100 μm. The abdominal skin of a hairless rat (HWY type, 7 weeks old) was set in a Franz diffusion cell, and each test preparation cut into a circle (φ14 mm) was applied. The receptor side was filled with phosphate buffered saline, and warm water at 37 ° C. was refluxed in the water jacket. The receptor liquid was sampled over time, and the amount of rasagiline permeated through the skin was measured by liquid chromatography. From the results, the transdermal absorption rate (Flux: μg / cm 2) at 8 hours and 16 hours after the test was started. / H) was calculated. Table 5 shows the results.
表5に示す結果より、メシル酸ラサギリンの遊離塩基の変換に必要な添加剤を配合しない比較例7の製剤は、薬物の皮膚透過性が低く、実施例1の20分の1以下であった。すなわち、本発明の貼付剤は、弱塩基性モノマーを共重合した星型アクリル系ブロックポリマーの配合効果により、メシル酸ラサギリンが十分に遊離塩基に変換され、それにより優れた薬物経皮吸収性を示している。また、実施例1の製剤は、EUDRAGIT E−100を配合することにより、塩基性薬物の塩から遊離塩基への変換を試みた比較例3の製剤と比較しても、同等以上の経皮吸収性を示した。 From the results shown in Table 5, the preparation of Comparative Example 7 in which the additive required for conversion of the free base of rasagiline mesylate was not blended had a low skin permeability of the drug, which was less than 1/20 of that of Example 1. . That is, the patch of the present invention is characterized in that rasagiline mesylate is sufficiently converted to a free base due to the compounding effect of the star-shaped acrylic block polymer obtained by copolymerizing a weakly basic monomer, thereby providing excellent drug transdermal absorption. Is shown. In addition, the formulation of Example 1 was compared with the formulation of Comparative Example 3 in which EUDRAGIT E-100 was blended to try to convert a salt of a basic drug to a free base. Showed sex.
〔試験例5〕:ウサギ皮膚一次刺激性試験
実施例1の製剤についてウサギ皮膚一次刺激性試験を行った。除毛したウサギ背部に製剤を24時間貼付し、剥離後1時間目、24時間目および48時間目の皮膚症状から刺激指数(P.I.I)を求めた。結果およびその評価基準を、それぞれ表6、および表7に示す。[Test Example 5]: Rabbit skin primary irritation test The preparation of Example 1 was subjected to a rabbit skin primary irritation test. The preparation was stuck on the back of the dehaired rabbit for 24 hours, and the irritation index (PII) was determined from the skin symptoms at 1, 24, and 48 hours after peeling. The results and evaluation criteria are shown in Tables 6 and 7, respectively.
表6に示す結果から、本発明の貼付剤は、皮膚刺激性が非常に低い製剤であることが判明した。すなわち、本発明の貼付剤は、塩基性薬物の塩を遊離塩基に変換するための塩基性添加物の配合が不要であるから、塩基性添加物自体の持つ皮膚刺激、および塩基性添加物と塩基性薬物の塩の反応により生成する塩基性塩による皮膚刺激が起こらず、非常に安全性の高い貼付剤であることが確認できた。 From the results shown in Table 6, it was found that the patch of the present invention was a preparation having extremely low skin irritation. That is, since the patch of the present invention does not require the addition of a basic additive for converting a salt of a basic drug into a free base, skin irritation possessed by the basic additive itself, and the basic additive Skin irritation due to the basic salt generated by the reaction of the salt of the basic drug did not occur, confirming that the patch was extremely safe.
〔アクリル粘着剤の調製〕
〔製造例2〕
2段階目の別反応:粘着剤用ポリマーの合成
温度計、撹拌機、不活性ガス導入管、還流冷却器および滴下ロートを備えた4つ口フラスコに製造例1で得られた中間ポリマー溶液(A1)13.70部、アクリル酸ブチル15.04部、アクリル酸2−エチルヘキシル6.16部、酢酸ビニル0.99部、メタクリル酸ジメチルアミノエチル2.47部、及び溶剤として酢酸エチル11.5部を仕込んだ。窒素気流下に撹拌し、83±2℃に保って重合開始剤としてV−601溶液(V−601の0.03部と酢酸エチル1部の混合物)を加えて重合を開始させた。反応開始から10分後に中間ポリマー溶液(A1)16.74部、アクリル酸ブチル18.38部、アクリル酸2−エチルヘキシル7.53部、酢酸ビニル1.21部、メタクリル酸ジメチルアミノエチル3.01部、及び溶剤として酢酸エチル11部からなるモノマー混合物と、V−601溶液(V−601:0.02部および酢酸エチル4部の混合物)とを80分かけて滴下し、還流下で制御しながら反応を行った。滴下終了後に酢酸エチル1部添加し、さらに3時間30分反応を続けた。その後、ブースターとしてV−601溶液(V−601:0.08部および酢酸エチル4部の混合物)を1時間かけて滴下し、さらに還流下で10時間反応を続けた。その後、希釈溶剤として酢酸エチルを30.3部添加し、冷却し粘着剤用ポリマー溶液(B2)を得た。得られたポリマー溶液(B2)は、不揮発分48.0%、粘度682mPa・s、数平均分子量が37,000、重量平均分子量が117,000であった。(Preparation of acrylic adhesive)
[Production Example 2]
Another reaction in the second step: Synthesis of polymer for pressure-sensitive adhesive The intermediate polymer solution obtained in Production Example 1 in a four-necked flask equipped with a thermometer, a stirrer, an inert gas introduction tube, a reflux condenser, and a dropping funnel ( A1) 13.70 parts, butyl acrylate 15.04 parts, 2-ethylhexyl acrylate 6.16 parts, vinyl acetate 0.99 parts, dimethylaminoethyl methacrylate 2.47 parts, and ethyl acetate 11.5 as a solvent The department was charged. The mixture was stirred under a nitrogen stream, and kept at 83 ± 2 ° C., and a V-601 solution (a mixture of 0.03 part of V-601 and 1 part of ethyl acetate) was added as a polymerization initiator to initiate polymerization. Ten minutes after the start of the reaction, 16.74 parts of the intermediate polymer solution (A1), 18.38 parts of butyl acrylate, 7.53 parts of 2-ethylhexyl acrylate, 1.21 parts of vinyl acetate, and 3.01 parts of dimethylaminoethyl methacrylate Parts, a monomer mixture consisting of 11 parts of ethyl acetate as a solvent, and a V-601 solution (a mixture of 0.02 parts of V-601 and 4 parts of ethyl acetate) were added dropwise over 80 minutes, and the mixture was controlled under reflux. The reaction was carried out. After completion of the dropwise addition, 1 part of ethyl acetate was added, and the reaction was further continued for 3 hours and 30 minutes. Thereafter, a V-601 solution (V-601: a mixture of 0.08 parts and 4 parts of ethyl acetate) was added dropwise as a booster over 1 hour, and the reaction was further continued under reflux for 10 hours. Thereafter, 30.3 parts of ethyl acetate was added as a diluting solvent, followed by cooling to obtain a polymer solution for an adhesive (B2). The obtained polymer solution (B2) had a nonvolatile content of 48.0%, a viscosity of 682 mPa · s, a number average molecular weight of 37,000 and a weight average molecular weight of 117,000.
〔製造例3〕
2段階目の別反応:粘着剤用ポリマーの合成
温度計、撹拌機、不活性ガス導入管、還流冷却器および滴下ロートを備えた4つ口フラスコに製造例1で得られた中間ポリマー溶液(A1)12.17部、アクリル酸ブチル14.43部、アクリル酸2−エチルヘキシル5.48部、酢酸ビニル0.88部、メタクリル酸ジメチルアミノエチル1.10部、テトラエチレングリコールジアクリレートを0.035部、及び溶剤として酢酸エチル11.5部を仕込んだ。窒素気流下に撹拌し、83±2℃に保って重合開始剤としてV−601溶液(V−601の0.02部と酢酸エチル1部の混合物)を加えて重合を開始させた。反応開始から10分後に中間ポリマー溶液(A1)18.26部、アクリル酸ブチル21.64部、アクリル酸2−エチルヘキシル8.22部、酢酸ビニル1.32部、メタクリル酸ジメチルアミノエチル1.64部、テトラエチレングリコールジアクリレートを0.053部及び溶剤として酢酸エチル11部からなるモノマー混合物と、V−601溶液(V−601:0.02部および酢酸エチル4部の混合物)とを80分かけて滴下し、還流下で制御しながら反応を行った。滴下終了後に酢酸エチル1部添加し、さらに3時間30分反応を続けた。その後、ブースターとしてV−601溶液(V−601:0.17部および酢酸エチル20部の混合物)を5時間かけて滴下し、さらに還流下で10時間反応を続けた。その後、希釈溶剤として酢酸エチルを14.3部添加し、冷却し粘着剤用ポリマー溶液(B3)を得た。得られたポリマー溶液(B3)は、不揮発分53.6%、粘度9,450mPa・s、数平均分子量が41,000、重量平均分子量が213,000であった。[Production Example 3]
Another reaction in the second step: Synthesis of polymer for pressure-sensitive adhesive The intermediate polymer solution obtained in Production Example 1 in a four-necked flask equipped with a thermometer, a stirrer, an inert gas introduction tube, a reflux condenser, and a dropping funnel ( A1) 12.17 parts, 14.43 parts of butyl acrylate, 5.48 parts of 2-ethylhexyl acrylate, 0.88 part of vinyl acetate, 1.10 parts of dimethylaminoethyl methacrylate, and 0.10 part of tetraethylene glycol diacrylate. 035 parts and 11.5 parts of ethyl acetate as a solvent were charged. The mixture was stirred under a nitrogen stream, and kept at 83 ± 2 ° C., a polymerization initiator V-601 solution (a mixture of 0.02 part of V-601 and 1 part of ethyl acetate) was added to initiate polymerization. Ten minutes after the start of the reaction, 18.26 parts of the intermediate polymer solution (A1), 21.64 parts of butyl acrylate, 8.22 parts of 2-ethylhexyl acrylate, 1.32 parts of vinyl acetate, 1.64 parts of dimethylaminoethyl methacrylate. Parts, a monomer mixture consisting of 0.053 parts of tetraethylene glycol diacrylate and 11 parts of ethyl acetate as a solvent, and a V-601 solution (V-601: a mixture of 0.02 parts and 4 parts of ethyl acetate) for 80 minutes. The reaction was carried out while controlling under reflux. After completion of the dropwise addition, 1 part of ethyl acetate was added, and the reaction was further continued for 3 hours and 30 minutes. Thereafter, a V-601 solution (V-601: a mixture of 0.17 parts and 20 parts of ethyl acetate) was added dropwise as a booster over 5 hours, and the reaction was further continued under reflux for 10 hours. Thereafter, 14.3 parts of ethyl acetate was added as a diluting solvent, and the mixture was cooled to obtain a pressure-sensitive adhesive polymer solution (B3). The obtained polymer solution (B3) had a nonvolatile content of 53.6%, a viscosity of 9,450 mPa · s, a number average molecular weight of 41,000 and a weight average molecular weight of 213,000.
〔製造例4〕
2段階目の別反応:粘着剤用ポリマーの合成
温度計、撹拌機、不活性ガス導入管、還流冷却器および滴下ロートを備えた4つ口フラスコに製造例1で得られた中間ポリマー溶液(A1)12.17部、アクリル酸ブチル13.37部、アクリル酸2−エチルヘキシル5.48部、酢酸ビニル0.88部、ジメチルアミノプロピルアクリルアミド2.19部、及び溶剤として酢酸エチル11.5部を仕込んだ。窒素気流下に撹拌し、83±2℃に保って重合開始剤としてV−601溶液(V−601の0.02部と酢酸エチル1部の混合物)を加えて重合を開始させた。反応開始から10分後に中間ポリマー溶液(A1)18.26部、アクリル酸ブチル20.05部、アクリル酸2−エチルヘキシル8.22部、酢酸ビニル1.32部、ジメチルアミノプロピルアクリルアミド3.29部、及び溶剤として酢酸エチル11部からなるモノマー混合物と、V−601溶液(V−601:0.02部および酢酸エチル4部の混合物)とを80分かけて滴下し、還流下で制御しながら反応を行った。滴下終了後に酢酸エチル1部添加し、さらに3時間30分反応を続けた。その後、ブースターとしてV−601溶液(V−601:0.17部および酢酸エチル12部の混合物)を3時間かけて滴下し、さらに還流下で10時間反応を続けた。その後、希釈溶剤として酢酸エチルを63部添加し、冷却し粘着剤用ポリマー溶液(B4)を得た。得られたポリマー溶液(B4)は、不揮発分38.3%、粘度14,410mPa・sであった。なお、分子量測定においてポリマー溶液(B4)のTHF溶液試料が濾過工程で目詰まりし、測定はできなかった。[Production Example 4]
Another reaction in the second step: Synthesis of polymer for pressure-sensitive adhesive The intermediate polymer solution obtained in Production Example 1 in a four-necked flask equipped with a thermometer, a stirrer, an inert gas introduction tube, a reflux condenser, and a dropping funnel ( A1) 12.17 parts, butyl acrylate 13.37 parts, 2-ethylhexyl acrylate 5.48 parts, vinyl acetate 0.88 parts, dimethylaminopropyl acrylamide 2.19 parts, and 11.5 parts of ethyl acetate as a solvent Was charged. The mixture was stirred under a nitrogen stream, and kept at 83 ± 2 ° C., a polymerization initiator V-601 solution (a mixture of 0.02 part of V-601 and 1 part of ethyl acetate) was added to initiate polymerization. Ten minutes after the start of the reaction, 18.26 parts of the intermediate polymer solution (A1), 20.05 parts of butyl acrylate, 8.22 parts of 2-ethylhexyl acrylate, 1.32 parts of vinyl acetate, and 3.29 parts of dimethylaminopropylacrylamide And a monomer mixture consisting of 11 parts of ethyl acetate as a solvent and a V-601 solution (a mixture of 0.02 parts of V-601 and 4 parts of ethyl acetate) were added dropwise over 80 minutes, and the mixture was controlled under reflux. The reaction was performed. After completion of the dropwise addition, 1 part of ethyl acetate was added, and the reaction was further continued for 3 hours and 30 minutes. Thereafter, a V-601 solution (V-601: a mixture of 0.17 parts and 12 parts of ethyl acetate) was added dropwise as a booster over 3 hours, and the reaction was further continued under reflux for 10 hours. Thereafter, 63 parts of ethyl acetate was added as a diluting solvent, and the mixture was cooled to obtain a polymer solution (B4) for an adhesive. The obtained polymer solution (B4) had a nonvolatile content of 38.3% and a viscosity of 14,410 mPa · s. In the molecular weight measurement, the THF solution sample of the polymer solution (B4) was clogged in the filtration step, and the measurement could not be performed.
〔製造例5〕
粘着剤用ポリマーの別合成
温度計、撹拌機、不活性ガス導入管、還流冷却器および滴下ロートを備えた4つ口フラスコにアクリル酸ブチル14.09部、アクリル酸2−エチルヘキシル5.25部、酢酸ビニル0.84部、メタクリル酸ジメチルアミノエチル0.82部、テトラエチレングリコールジアクリレートを0.002部、及び溶剤として酢酸エチル31部を仕込んだ。窒素気流下に撹拌し、83±2℃に保って重合開始剤としてV−601溶液(V−601の0.03部と酢酸エチル1部の混合物)を加えて重合を開始させた。反応開始から10分後にアクリル酸ブチル32.87部、アクリル酸2−エチルヘキシル12.25部、酢酸ビニル1.96部、ジメチルアミノエチルメタクリレート1.91部、テトラエチレングリコールジアクリレートを0.005部及び溶剤として酢酸エチル21部からなるモノマー混合物と、V−601溶液(V−601:0.06部および酢酸エチル4部の混合物)とを80分かけて滴下し、還流下で制御しながら反応を行った。滴下終了後に酢酸エチル1部添加し、さらに3時間30分反応を続けた。その後、ブースターとしてV−601溶液(V−601:0.17部および酢酸エチル12部の混合物)を3時間かけて滴下し、さらに還流下で10時間反応を続けた。その後、希釈溶剤として酢酸エチルを20.3部添加し、冷却し粘着剤用ポリマー溶液(B5)を得た。得られたポリマー溶液(B5)は、不揮発分44.8%、粘度1,030mPa・s、数平均分子量が62,000、重量平均分子量が271,000であった。[Production Example 5]
Separate synthesis of polymer for pressure-sensitive adhesive 14.09 parts of butyl acrylate, 5.25 parts of 2-ethylhexyl acrylate in a four-necked flask equipped with a thermometer, stirrer, inert gas inlet tube, reflux condenser and dropping funnel 0.84 parts of vinyl acetate, 0.82 parts of dimethylaminoethyl methacrylate, 0.002 parts of tetraethylene glycol diacrylate, and 31 parts of ethyl acetate as a solvent. The mixture was stirred under a nitrogen stream, and kept at 83 ± 2 ° C., and a V-601 solution (a mixture of 0.03 part of V-601 and 1 part of ethyl acetate) was added as a polymerization initiator to initiate polymerization. Ten minutes after the start of the reaction, 32.87 parts of butyl acrylate, 12.25 parts of 2-ethylhexyl acrylate, 1.96 parts of vinyl acetate, 1.91 parts of dimethylaminoethyl methacrylate, and 0.005 parts of tetraethylene glycol diacrylate And a monomer mixture comprising 21 parts of ethyl acetate as a solvent and a V-601 solution (a mixture of 0.06 parts of V-601 and 4 parts of ethyl acetate) were added dropwise over 80 minutes, and the reaction was carried out under reflux while controlling. Was done. After completion of the dropwise addition, 1 part of ethyl acetate was added, and the reaction was further continued for 3 hours and 30 minutes. Thereafter, a V-601 solution (V-601: a mixture of 0.17 parts and 12 parts of ethyl acetate) was added dropwise as a booster over 3 hours, and the reaction was further continued under reflux for 10 hours. Thereafter, 20.3 parts of ethyl acetate was added as a diluting solvent, followed by cooling to obtain a polymer solution for an adhesive (B5). The obtained polymer solution (B5) had a nonvolatile content of 44.8%, a viscosity of 1,030 mPa · s, a number average molecular weight of 62,000 and a weight average molecular weight of 271,000.
〔製造例6〕
粘着剤用ポリマーの別合成
温度計、撹拌機、不活性ガス導入管、還流冷却器および滴下ロートを備えた4つ口フラスコにアクリル酸ブチル13.27部、アクリル酸2−エチルヘキシル5.25部、酢酸ビニル0.84部、メタクリル酸ジメチルアミノエチル1.64部、テトラエチレングリコールジアクリレートを0.002部、及び溶剤として酢酸エチル31部を仕込んだ。窒素気流下に撹拌し、83±2℃に保って重合開始剤としてV−601溶液(V−601の0.03部と酢酸エチル1部の混合物)を加えて重合を開始させた。反応開始から10分後にアクリル酸ブチル30.96部、アクリル酸2−エチルヘキシル12.25部、酢酸ビニル1.96部、ジメチルアミノエチルメタクリレート3.82部、テトラエチレングリコールジアクリレートを0.005部及び溶剤として酢酸エチル21部からなるモノマー混合物と、V−601溶液(V−601:0.06部および酢酸エチル4部の混合物)とを80分かけて滴下し、還流下で制御しながら反応を行った。滴下終了後に酢酸エチル1部添加し、さらに3時間30分反応を続けた。その後、ブースターとしてV−601溶液(V−601:0.17部および酢酸エチル12部の混合物)を3時間かけて滴下し、さらに還流下で10時間反応を続けた。その後、希釈溶剤として酢酸エチルを20.3部添加し、冷却し粘着剤用ポリマー溶液(B6)を得た。得られたポリマー溶液(B6)は、不揮発分45.2%、粘度509mPa・s、数平均分子量が53,000、重量平均分子量が202,000であった。[Production Example 6]
Separate synthesis of polymer for pressure sensitive adhesive 13.27 parts of butyl acrylate, 5.25 parts of 2-ethylhexyl acrylate in a four-necked flask equipped with a thermometer, stirrer, inert gas inlet tube, reflux condenser and dropping funnel 0.84 parts of vinyl acetate, 1.64 parts of dimethylaminoethyl methacrylate, 0.002 parts of tetraethylene glycol diacrylate, and 31 parts of ethyl acetate as a solvent. The mixture was stirred under a nitrogen stream, and kept at 83 ± 2 ° C., and a V-601 solution (a mixture of 0.03 part of V-601 and 1 part of ethyl acetate) was added as a polymerization initiator to initiate polymerization. Ten minutes after the start of the reaction, 30.96 parts of butyl acrylate, 12.25 parts of 2-ethylhexyl acrylate, 1.96 parts of vinyl acetate, 3.82 parts of dimethylaminoethyl methacrylate, and 0.005 part of tetraethylene glycol diacrylate And a monomer mixture comprising 21 parts of ethyl acetate as a solvent and a V-601 solution (a mixture of 0.06 parts of V-601 and 4 parts of ethyl acetate) were added dropwise over 80 minutes, and the reaction was carried out under reflux while controlling. Was done. After completion of the dropwise addition, 1 part of ethyl acetate was added, and the reaction was further continued for 3 hours and 30 minutes. Thereafter, a V-601 solution (V-601: a mixture of 0.17 parts and 12 parts of ethyl acetate) was added dropwise as a booster over 3 hours, and the reaction was further continued under reflux for 10 hours. Thereafter, 20.3 parts of ethyl acetate was added as a diluting solvent, and the mixture was cooled to obtain a pressure-sensitive adhesive polymer solution (B6). The obtained polymer solution (B6) had a nonvolatile content of 45.2%, a viscosity of 509 mPa · s, a number average molecular weight of 53,000 and a weight average molecular weight of 202,000.
(製造例7)
粘着剤用ポリマーの合成
温度計、撹拌機、不活性ガス導入管、還流冷却器および滴下ロートを備えた4つ口フラスコにアクリル酸ブチル13.27部、アクリル酸2−エチルヘキシル5.25部、酢酸ビニル0.84部、ジメチルアミノプロピルアクリルアミド1.64部、及び溶剤として酢酸エチル41部を仕込んだ。窒素気流下に撹拌し、83±2℃に保って重合開始剤としてV−601溶液(V−601の0.03部と酢酸エチル1部の混合物)を加えて重合を開始させた。反応開始から10分後にアクリル酸ブチル30.97部、アクリル酸2−エチルヘキシル12.25部、酢酸ビニル1.96部、ジメチルアミノプロピルアクリルアミド3.82部、及び溶剤として酢酸エチル31部からなるモノマー混合物と、V−601溶液(V−601:0.06部および酢酸エチル4部の混合物)とを80分かけて滴下し、還流下で制御しながら反応を行った。滴下終了後に酢酸エチル1部添加し、さらに3時間30分反応を続けた。その後、ブースターとしてV−601溶液(V−601:0.17部および酢酸エチル12部の混合物)を3時間かけて滴下し、さらに還流下で10時間反応を続けた。その後、希釈溶剤として酢酸エチルを20.3部添加し、冷却し粘着剤用ポリマー溶液(B7)を得た。得られたポリマー溶液(B7)は、不揮発分39.1%、粘度4,090mPa・sであった。なお、分子量測定においてポリマー溶液(B7)のTHF溶液試料が濾過工程で目詰まりし、測定はできなかった。(Production Example 7)
Synthesis of polymer for pressure sensitive adhesive 13.27 parts of butyl acrylate, 5.25 parts of 2-ethylhexyl acrylate in a four-necked flask equipped with a thermometer, a stirrer, an inert gas inlet tube, a reflux condenser and a dropping funnel, 0.84 parts of vinyl acetate, 1.64 parts of dimethylaminopropylacrylamide, and 41 parts of ethyl acetate as a solvent were charged. The mixture was stirred under a nitrogen stream, and kept at 83 ± 2 ° C., and a V-601 solution (a mixture of 0.03 part of V-601 and 1 part of ethyl acetate) was added as a polymerization initiator to initiate polymerization. 10 minutes after the start of the reaction, a monomer composed of 30.97 parts of butyl acrylate, 12.25 parts of 2-ethylhexyl acrylate, 1.96 parts of vinyl acetate, 3.82 parts of dimethylaminopropylacrylamide, and 31 parts of ethyl acetate as a solvent The mixture and a V-601 solution (a mixture of 0.06 parts of V-601 and 4 parts of ethyl acetate) were added dropwise over 80 minutes, and the reaction was carried out while controlling under reflux. After completion of the dropwise addition, 1 part of ethyl acetate was added, and the reaction was further continued for 3 hours and 30 minutes. Thereafter, a V-601 solution (V-601: a mixture of 0.17 parts and 12 parts of ethyl acetate) was added dropwise as a booster over 3 hours, and the reaction was further continued under reflux for 10 hours. Thereafter, 20.3 parts of ethyl acetate was added as a diluting solvent, and the mixture was cooled to obtain a pressure-sensitive adhesive polymer solution (B7). The obtained polymer solution (B7) had a nonvolatile content of 39.1% and a viscosity of 4,090 mPa · s. In the molecular weight measurement, the THF solution sample of the polymer solution (B7) was clogged in the filtration step, and the measurement could not be performed.
また、上記製造例2〜7で使用される特性は、上記製造例1に記載の方法によって測定・評価した。 The properties used in Production Examples 2 to 7 were measured and evaluated by the method described in Production Example 1.
〔貼付剤の調製〕
〔実施例3〕
アクリル粘着剤を製造例2に記載の粘着剤に変更した以外は、下記表8に示す処方構成で、上記実施例1の製法に従い、実施例3の医療用貼付剤を製造した。(Preparation of patch)
[Example 3]
A medical patch of Example 3 was produced in accordance with the production method of Example 1 above with the formulation shown in Table 8 below, except that the acrylic adhesive was changed to the adhesive described in Production Example 2.
〔実施例4〕
アクリル粘着剤を製造例3に記載の粘着剤に変更した以外は、下記表8に示す処方構成で、上記実施例1の製法に従い、実施例4の医療用貼付剤を製造した。[Example 4]
A medical patch of Example 4 was produced according to the production method of Example 1 above, with the formulation shown in Table 8 below, except that the acrylic adhesive was changed to the adhesive described in Production Example 3.
〔実施例5〕
アクリル粘着剤を製造例4に記載の粘着剤に変更した以外は、下記表8に示す処方構成で、上記実施例1の製法に従い、実施例5の医療用貼付剤を製造した。[Example 5]
A medical patch of Example 5 was produced according to the production method of Example 1 above, with the formulation shown in Table 8 below, except that the acrylic adhesive was changed to the adhesive described in Production Example 4.
〔比較例11〕
アクリル粘着剤を製造例5に記載の粘着剤に変更した以外は、下記表8に示す処方構成で、上記実施例1の製法に従い、比較例11の医療用貼付剤を製造した。[Comparative Example 11]
A medical patch of Comparative Example 11 was produced in accordance with the production method of Example 1 above, with the formulation shown in Table 8 below, except that the acrylic adhesive was changed to the adhesive described in Production Example 5.
〔比較例12〕
アクリル粘着剤を製造例6に記載の粘着剤に変更した以外は、下記表8に示す処方構成で、上記実施例1の製法に従い、比較例12の医療用貼付剤を製造した。[Comparative Example 12]
A medical patch of Comparative Example 12 was produced in accordance with the production method of Example 1 above, using the formulation shown in Table 8 below, except that the acrylic adhesive was changed to the adhesive described in Production Example 6.
〔比較例13〕
アクリル粘着剤を製造例7に記載の粘着剤に変更した以外は、下記表8に示す処方構成で、上記実施例1の製法に従い、比較例13の医療用貼付剤を製造した。[Comparative Example 13]
A medical patch of Comparative Example 13 was produced in accordance with the production method of Example 1 above, using the formulation shown in Table 8 below, except that the acrylic adhesive was changed to the adhesive described in Production Example 7.
実施例3〜5及び比較例11〜13に記載の医療用貼付剤の組成、並びに当該医療用貼付剤についての薬物に対する塩基性モノマーのモル比率、タック力、剥離力、及び保持力を下記の表8に示す。
〔試験例5〕:プローブタック試験
本発明の医療用貼付剤の粘着力(タック力)を評価するため、試験例1の方法に従い、実施例3〜5、および比較例11〜13について、プローブタック試験を行った。その結果を表8に示す。なお、本試験においては、比較例の製剤に凝集破壊を起こす試料が散見されたため、物性評価は、タック力と膏体の凝集破壊の有無を総合的に評価し、表9に示す3段階の評価基準で行った。
〔試験例6〕:剥離試験
本発明の医療用貼付剤の粘着力(剥離力)を評価するため、試験例2の方法に従い、実施例3〜5、及び比較例11〜13について、剥離試験を行った。その結果を表8に示す。[Test Example 6]: Peeling test In order to evaluate the adhesive strength (peeling force) of the medical patch of the present invention, peeling tests were performed on Examples 3 to 5 and Comparative Examples 11 to 13 according to the method of Test Example 2. Was done. Table 8 shows the results.
〔試験例7〕:保持力試験
本発明の医療用貼付剤の保持力を評価するため、実施例3〜5、および比較例11〜13について、保持力試験を行った。供試製剤を1cm×5cmに調整し、剥離フィルムを剥がし、長手方向の端部より1cmのところで折り返し、膏体面同士を重ね合わせた。次に膏体面が露出している残りの3cmの部分をSUS304−BA試験板に貼り付け、2kgのローラーで毎分300mmの速度で貼付剤上を往復させ、20分間放置した。その後、膏体面同士を重ね合した部分に1kgの重りを取り付け、試験製剤が完全に試験板から剥がれ落ちるまでの経過時間の長さで保持力を評価した。但し試験開始後2時間(7200秒を上限とした。各測定値を表8に示した。[Test Example 7]: Holding force test In order to evaluate the holding force of the medical patch of the present invention, a holding force test was performed on Examples 3 to 5 and Comparative Examples 11 to 13. The test preparation was adjusted to 1 cm × 5 cm, the release film was peeled off, and it was folded back at 1 cm from the end in the longitudinal direction, and the plaster surfaces were overlapped. Next, the remaining 3 cm portion where the plaster surface was exposed was attached to a SUS304-BA test plate, and was reciprocated on the patch at a speed of 300 mm / min with a 2 kg roller and left for 20 minutes. Thereafter, a weight of 1 kg was attached to the portion where the plaster surfaces were overlapped with each other, and the holding power was evaluated based on the length of time elapsed until the test preparation completely peeled off the test plate. However, 2 hours after the start of the test (the upper limit was 7200 seconds. Table 8 shows the measured values.
上記各試験結果より、本発明の貼付剤は、各比較例の貼付剤と比較し、タック力、剥離力、および保持力において優れた物性を示した。特に保持力においては比較例の製剤より格段に優れていることが判明した。これはすなわち、本発明の弱塩基性モノマーを共重合した星型アクリル系ブロックポリマーが、本貼付剤に優れた凝集性および粘着性を付与しているためであることが理解できる。 From the above test results, the patch of the present invention showed excellent physical properties in tack force, peeling force, and holding force as compared with the patches of Comparative Examples. In particular, it was found that the holding power was significantly superior to the preparation of Comparative Example. That is, it can be understood that the star-shaped acrylic block polymer obtained by copolymerizing the weakly basic monomer of the present invention imparts excellent cohesiveness and adhesiveness to the patch.
〔試験例8〕:薬物放出試験
本発明の医療用貼付剤の薬物放出性を評価するため、実施例3、および比較例12について、薬物放出試験を行った。供試製剤を直径14mmの円形(Φ14mm)に打ち抜き、各試験製剤の支持体側を、両面テープを用いてスライドガラスに貼り付け、固定した。スライドガラスに固定した試験製剤は、予めレセプター漕に試験液*を満たしたフランツ型拡散セルに、粘着層側をレセプター側としてセットし、経時的に試験液をサンプリングし、試験液中に放出されたラサギリン量を液体クロマトグラフ法により測定し、製剤から放出されたラサギリンの比率である放出率(%)**を算出した。結果を表10に示す。
*試験液:40%ポリエチレングリコール/10%イソプロパノール/50%リン酸緩衝生理食塩水混液
**放出率:試験開始後6時間目の試験液中のラサギリン量(mg)/供試製剤(Φ14mm)中のラサギリン含量(mg)*100
* Test solution: 40% polyethylene glycol / 10% isopropanol / 50% phosphate buffered saline mixed solution
** Release rate: Rasagiline content (mg) in test solution 6 hours after start of test / Rasagiline content (mg) in test preparation (Φ14 mm) * 100
上記各試験結果より、本発明の貼付剤は、比較例の貼付剤と比べ、優れた薬物放出性を示し、製剤の物性と薬物放出性とを両立できる製剤であることが理解される。 From the results of the above tests, it is understood that the patch of the present invention is a preparation that exhibits excellent drug release properties as compared with the patch of the comparative example, and can achieve both the physical properties of the preparation and the drug release properties.
本発明の星型アクリル系ブロックポリマーを粘着性ポリマーとして含む医療用貼付剤によれば、貼付剤の粘着物性、保持特性といった製剤特性を損なうことなく、また皮膚刺激性が低く、薬物放出性が高い医療用貼付剤を提供することができる。 According to the medical patch containing the star-shaped acrylic block polymer of the present invention as an adhesive polymer, the adhesive properties of the patch, without impairing the formulation properties such as retention properties, and also have low skin irritation and low drug release. A high medical patch can be provided.
Claims (12)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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JP2015193844 | 2015-09-30 | ||
JP2015193844 | 2015-09-30 | ||
PCT/JP2016/079056 WO2017057693A1 (en) | 2015-09-30 | 2016-09-30 | Adhesive polymer and medical adhesive patch |
Publications (2)
Publication Number | Publication Date |
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JPWO2017057693A1 JPWO2017057693A1 (en) | 2018-09-06 |
JP6639513B2 true JP6639513B2 (en) | 2020-02-05 |
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US (1) | US11077069B2 (en) |
EP (1) | EP3357945A4 (en) |
JP (1) | JP6639513B2 (en) |
KR (1) | KR20180059870A (en) |
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WO2017018321A1 (en) * | 2015-07-27 | 2017-02-02 | 久光製薬株式会社 | Method for manufacturing asenapine-containing patch |
US10806705B2 (en) | 2015-07-27 | 2020-10-20 | Hisamitsu Pharmaceutical Co., Inc. | Asenapine-containing patch |
JP2021028294A (en) * | 2017-09-22 | 2021-02-25 | 株式会社 メドレックス | Topical agent composition containing hydromorphone as medicinal component |
CN110115710B (en) * | 2018-02-06 | 2022-12-13 | 北京泰德制药股份有限公司 | A transdermal preparation for the treatment of asthma |
KR102295720B1 (en) | 2019-10-29 | 2021-08-31 | (주)아팩 | Aqueous adhesive composition for medical adhesive and medical adhesive sheet using thereof |
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JPS463398Y1 (en) | 1970-02-18 | 1971-02-05 | ||
JPS4916200B1 (en) | 1970-12-15 | 1974-04-20 | ||
JPH0745400B2 (en) | 1986-03-29 | 1995-05-17 | 日東電工株式会社 | External pharmaceutical preparation |
US4954343A (en) | 1986-03-29 | 1990-09-04 | Nitto Electric Industrial Co., Ltd. | Dermal pharmaceutical preparations |
JPH06199952A (en) * | 1992-12-28 | 1994-07-19 | Nippon Shokubai Co Ltd | Star polymer and its production |
DE69420131D1 (en) | 1993-12-24 | 1999-09-23 | Nippon Catalytic Chem Ind | BLOCK POLYMER, THERMOPLASTIC ADDITION POLYMER, THEIR PRODUCTION PROCESS AND USE |
JP2842782B2 (en) * | 1993-12-24 | 1999-01-06 | 株式会社日本触媒 | Star-shaped block polymer and method for producing the same |
JP3465833B2 (en) * | 1995-06-07 | 2003-11-10 | 株式会社日本触媒 | Solvent type pressure sensitive adhesive composition |
JP3385177B2 (en) | 1997-04-10 | 2003-03-10 | 株式会社日本触媒 | Star-shaped block polymer and method for producing the same |
GB9714650D0 (en) * | 1997-07-11 | 1997-09-17 | Strakan Ltd | Block copolymer |
JP2001139646A (en) * | 1999-11-12 | 2001-05-22 | Nippon Shokubai Co Ltd | Acrylic block polymer and its use and production method |
EP1290036A1 (en) * | 2000-06-02 | 2003-03-12 | National Starch and Chemical Investment Holding Corporation | Water soluble ampiphilic heteroarm star polymers and their use as emulsion stabilizers in emulsion polymerization |
EP1290102A1 (en) | 2000-06-02 | 2003-03-12 | National Starch and Chemical Investment Holding Corporation | The use of star-branched polymers in pressure sensitive adhesives |
CN100379833C (en) | 2002-07-26 | 2008-04-09 | 阿托菲纳公司 | Adhesive composition for a humid medium based on block copolymers comprising at least one hydrophilic block |
WO2004062600A2 (en) * | 2003-01-08 | 2004-07-29 | Lectec Corporation | Antiviral patch |
EP1580202A1 (en) * | 2004-03-25 | 2005-09-28 | Nippon Shokubai Co., Ltd. | Acrylic block copolymer and uses thereof |
JP4603398B2 (en) | 2004-03-25 | 2010-12-22 | 株式会社日本触媒 | Adhesive for skin application and its use |
JP4916200B2 (en) * | 2005-03-25 | 2012-04-11 | 株式会社日本触媒 | Skin adhesive material and method for producing the same |
JP4744481B2 (en) | 2007-06-01 | 2011-08-10 | 株式会社日本触媒 | Acrylic block polymer and use and production method thereof |
JP5675225B2 (en) | 2009-09-01 | 2015-02-25 | 久光製薬株式会社 | Patch preparation |
EA023786B1 (en) * | 2010-04-30 | 2016-07-29 | ТЕЙКОКУ ФАРМА ЮЭсЭй, ИНК. | Propynylaminoindan transdermal compositions |
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CA3000619C (en) | 2024-01-16 |
AU2016332531B2 (en) | 2021-05-20 |
TWI775728B (en) | 2022-09-01 |
EP3357945A1 (en) | 2018-08-08 |
CN108290990A (en) | 2018-07-17 |
TW201734066A (en) | 2017-10-01 |
US11077069B2 (en) | 2021-08-03 |
KR20180059870A (en) | 2018-06-05 |
HK1255948A1 (en) | 2019-09-06 |
US20180280315A1 (en) | 2018-10-04 |
WO2017057693A1 (en) | 2017-04-06 |
EP3357945A4 (en) | 2019-06-26 |
CA3000619A1 (en) | 2017-04-06 |
CN108290990B (en) | 2022-02-01 |
JPWO2017057693A1 (en) | 2018-09-06 |
AU2016332531A1 (en) | 2018-05-10 |
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